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CN101906106A - New heterogeneous ring compound as the HSP90-inhibitor - Google Patents

New heterogeneous ring compound as the HSP90-inhibitor Download PDF

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CN101906106A
CN101906106A CN2010101575972A CN201010157597A CN101906106A CN 101906106 A CN101906106 A CN 101906106A CN 2010101575972 A CN2010101575972 A CN 2010101575972A CN 201010157597 A CN201010157597 A CN 201010157597A CN 101906106 A CN101906106 A CN 101906106A
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heteroaryl
alkyl group
aryl
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斯里尼瓦斯·R·卡西布哈特拉
马库斯·F·贝姆
凯文·D·翁
马科·A·比亚蒙特
史建栋
让·伊夫·勒布拉齐代克
张琳
戴维·赫斯特
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Conforma Therapeutics Corp
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Abstract

The present invention relates to the compound of formula I representative, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure 201010157597.2_AB_0
And a kind of pharmaceutical composition, comprise one or more pharmaceutically acceptable excipient and above-claimed cpds.And above-claimed cpd or pharmaceutical composition suppress the method for HSP90, and treatment suffers from the method for individuality of the illness of HSP90 mediation.

Description

New heterogeneous ring compound as the HSP90-inhibitor
The application is to be on September 20th, 2004 applying date, and application number is 2004800335230, and denomination of invention is divided an application for the application of " as the new heterogeneous ring compound of HSP90-inhibitor ".
Invention field
Generally speaking, the present invention relates to heterogeneous ring compound and related compound and broad spectrum purposes thereof, for example be used to suppress heat shock protein 90 (HSP90) thereby the disease of treatment or prevention HSP90-mediation.
Background of invention
HSP90 is ubiquitous chaperone protein, and folding, activate and combination of its participation range protein comprises that the participation signal conducts, the cell cycle is controlled and the main protein of transcriptional regulatory.The researchist has reported HSP90 chaperone protein and important signal-proteins, for example steroid hormone receptor and protein kinase, comprise for example Raf-1, EGFR, v-Src family kinases, Cdk4 and ErbB-2 (Buchner J.TIBS 1999,24,136-141; Stepanova, L. etc., Genes Dev.1996,10,1491-502; Dai, K. etc., J.Biol.Chem.1966,271,22030-4) relevant.Research shows further that also certain is total to-companion, for example HSP70, p60/Hop/Stil, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilin, p23 and p50 have the function that helps HSP90 (referring to, Caplan for example, A.Trends in Cell Biol.1999,9,262-68).
It is believed that the ansamycins microbiotic, for example Antibiotic TAN 420F (HA), geldanamycin (GM) and 17-allyl amino geldanamycin mycin (17-AAG) the terminal bag of the N-by HSP90 combining closely, and then make usually and the interactional substrate instability of HSP90, thereby performance antitumous effect (Stebbins, C. etc., Cell 1997,89,239-250).This bag high conservative and have weak homology (Stebbins, C. etc., supra for the ATP-binding site of dna gyrase; Grenert, J.P. etc., J.Biol.Chem., 1997,272,23843-50).In addition, ATP and ADP show with low-affinity and combine with this bag and have weak atpase activity (Cell 1997,90,65-75 for Proromou, C. etc.; Panaretou, B. etc., EMBO J.1998,17,4828-36).It is folding that research has in vitro and in vivo illustrated that the terminal bag of this N-is occupied the function and the arrestin matter that then change HSP90 by ansamycins and other HSP90 inhibitor.Under high density, ansamycins and other HSP90 inhibitor show (Scheibel, T.H. etc., Proc.Natl.Acad.Sci., the U.S. 1999,96, the 1297-302 of combining that can prevent protein substrate and HSP90; Schulte, T..W etc., J.Biol.Chem.1995,270,24585-8; Whitesell, L. etc., the Proc.Natl.Acad.Sci. U.S. 1994,91,8324-8328).Prove that also ansamycins can suppress ATP-dependent release (Schneider, C.L. etc., Proc.Natl.Acad.Sci., the U.S. 1996,93, the 14536-41 of companion's-relevant protein substrate; Sepp-Lorenzino etc., J.Biol.Chem.1995,270,16580-16587).Under any situation of the two, described substrate in proteasome by ubiquitin-dependency process degrade (Schneider, C.L., supra; Sepp-Lorenzino, L. etc., J.Biol.Chem.1995,270,16580-16587; Whitesell, L. etc., Proc.Natl.Acad.Sci., the U.S. 1994,91,8324-8328).
The instability effect of HSP90 substrate occurs in tumour and the untransformed cell, and shows the subclass of the conditioning agent that signals effectively especially, and described Signal Regulation jizi for making dumplings collection for example is Raf (Schulte, T.W. etc., Biochem.Biophys.Res.Commun.1997,239,655-9; Schulte, T.W. etc., J.Biol.Chem.1995,270,24585-8), nuclear steroid receptor (Segnitz, B.; U.Gehring J.Biol.Chem.1997,272,18694-18701; Smith, D.F. etc., Mol.Cell.Biol.1995,15,6804-12), v-Src (Whitesell, L. etc., Proc.Natl.Acad.Sci., the U.S. 1994,91,8324-8328) and certain transmembrane Tyrosylprotein kinase (Sepp-Lorenzino, L. etc., J.Biol.Chem.1995,270,16580-16587), for example EGF acceptor (EGFR) and HER2/Neu (Hartmann, F. etc., Int.J.Cancer.1997,70,221-9; Miller, P. etc., Cancer Res.1994,54,2724-2730; Mimnaugh, E.G. etc., J.Biol.Chem.1996,271,22796-901; Schnur, R. etc., J.Med.Chem.1995,38,3806-3812), CDK4 and mutant p53.Erlichman etc., Proc.AACR 2001,42, summary 4474.These the proteinic losses of ansamycins-inductive cause certain selectivity of regulating approach to be interrupted, and cause stopping (Muise-Heimericks, R.C. etc., J.Biol.Chem.1998 through the specified phase generation growth of cell in the cell cycle of processing like this, 273,29864-72) and apoptosis, and/or differentiation (Vasilevskaya, A. etc., Cancer Res., 1999,59,3935-40).Therefore, ansamycins brings very big hope for broad variety cancer and treating and/or preventing of proliferative disorders, returns traditional microbiotic and brings hope.But it is insoluble relatively to make it be difficult to preparation and administration, and it is difficult for synthetic and must produces by fermenting to small part at present.In addition, the dose limitation toxicity of ansamycins is determined by liver.
Except anticancer and anti-tumor activity, the HSP90 inhibitor also is expected to be used in various other purposes, comprise medicine as antiphlogiston, infectivity resistant disease, be used for the treatment of autoimmunity medicine, be used for the treatment of the medicine of apoplexy, local asphyxia, multiple sclerosis, heart trouble, the illness relevant with central nervous system and can be used for promoting neurotization medicine (referring to, Rosen etc. for example, WO 02/09696 (PCT/US01/23640); Degranco etc., WO 99/51223 (PCT/US99/07242); Gold, United States Patent (USP) 6,210,974B1; DeFranco etc., United States Patent (USP) 6,174,875.Overlap with above-mentioned document, also reported with the HSP90 inhibitor in the document and can also treat the fibrosis illness, it includes but not limited to scleroderma, polymyositis, system's lupus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis and pulmonary fibrosis.Strehlow，WO?02/02123(PCT/US01/20578)。Further, the HSP90 regulating effect, conditioning agent and uses thereof is also at application No.PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805, PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303, PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069, PCT/US02/35938, PCT/US02/39993,60/293,246,60/371,668,60/335,391,60/128,593,60/337,919,60/340,762,60/359, report in 484 and 60/331,893.
For example in PCT/US02/35069 and PCT/US02/36075, report demonstration HSP90 recently and suppressed active purine derivative.The purine part all is the bioisostere that can accept well for various ATP-dependency molecular targets, referring to JP 10025294; US patent 4,748,177; US patent 4,772,606; US patent 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; EP0178178; Eur.J.Med.Chena.1994,29 (1), 3-9; And J.Het.Chem.1990,27 (5), 1409.But report does not have effectiveness, the selectivity of hope and has the compound that effectively suppresses the required pharmaceutical properties of HSP90 in vivo yet.Therefore, still need other new and effective HSP90 inhibitor, it should satisfy the biology and the pharmaceutical standards of carrying out the desired harshness of human clinical trial.
Summary of the invention
The present invention relates to heterogeneous ring compound, relate in particular to, for example show the heterogeneous ring compound of extensive practicality and relevant analogue with prevention HSP90-dependence disease by suppressing HSP90 and treatment.
On the one hand, the present invention includes as shown in the formula the compound that specifies among A, I, IA-E, II, IIA-D, III, IIIA-B and IV and the IVA and related analogs and prepared according to the methods of the invention heterogeneous ring compound.Stereoisomer form is also included within the scope of the present invention, it comprises independent enantiomer and diastereomer body, racemic mixture and the non-enantiomer mixture of these compounds, and polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt and prodrug.The steric isomer of The compounds of this invention can pass through standard method for splitting, for example fractional crystallization and chiral column chromatographic separation.
On the one hand, the invention provides formula A compound to inhibition HSP90 and/or treatment and prevention HSP90-dependence disease demonstration practicality, or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug.
Figure GSA00000083249100041
Formula A
Various types of and the subclass of formula A compound within the scope of the present invention has been described among Fig. 1.Especially, the invention provides the compound of formula I-IV.
Figure GSA00000083249100051
On the other hand, the invention provides suppressing the compound that HSP90 and/or treatment and prevention HSP90-dependence disease show practicality, or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, described compound is prepared by following method, comprising:
Make the reaction of formula Y compound and formula Z compound, wherein:
Y is shown in following any one structural formula:
Figure GSA00000083249100052
Z is L 1-R 4-R 5
On the other hand, the present invention relates to be used for the treatment of or prevent the pharmaceutical composition of HSP90-dependence disease, it comprises compound of the present invention, especially the compound of formula A, I, II, III and IV and related analogs, and the compound that forms by method of the present invention, and polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug and one or more drug excipients.
On the other hand, feature of the present invention also is a kind of formula A, I, II, III or IV compound by comprising medicine effective quantity, or the pharmaceutical composition of its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug delivers medicine to the method that individuality is treated the individuality of the illness with HSP90-mediation.
In one embodiment, the invention provides a kind of method for the treatment of for the individuality of suffering from the inflammatory diseases of being selected from, infection, autoimmune disorder, apoplexy, local asphyxia, cardiac conditions, nervous disorders, fibrosis illness, proliferative disorders, tumour, leukemia, vegetation, cancer, cancer knurl, metabolic trouble and malignant disease illness.
In another embodiment, the invention provides a kind of for suffering from the fibrosis illness, the individuality of scleroderma, polymyositis, system's lupus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis and the pulmonary fibrosis method for the treatment of for example.
In another embodiment, the invention provides a kind of combination therapy, comprise formula A, I, II, III or IV compound and related analogs according to aforesaid either side or embodiment administration medicine significant quantity, or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt and prodrug and at least a therapeutical agent that is selected from cytotoxic agent, anti-angiogenic agent and antineoplastic agent.The optional self-alkylation agent of antineoplastic agent, anti--metabolite, epipodophyllotoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological respinse modifier and growth inhibitor, hormone/anti--hormonotherapy agent and hemopoieticgrowth factor.
Above-mentioned either side of the present invention in practice and embodiment can combine.
The individualized compound that is used for writing out a prescription, method and composition do not hinder the use of other material, the step that does not specify and reagent, it should be understood by one skilled in the art that other step and compound also can advantageously be combined in the spirit of all respects of the present invention and embodiment.
Superiority of the present invention depends on concrete aspect and embodiment, and can comprise one or more superiority: with respect to for the compound that has existed in the identical or different HSP90 inhibitor, it is easy to synthetic and/or preparation, dissolving and IC 50
The accompanying drawing summary
Fig. 1 has shown various exemplary types and the subtype of formula A.
Detailed description of the preferred embodiments
I. definition
" pharmaceutically acceptable derivates or prodrug " refers to any pharmacy acceptable salt, the ester of The compounds of this invention, salt or other derivative of ester, and it can provide compound of the present invention or its pharmaceutical activity metabolite or residuum directly or indirectly when delivering medicine to the receptor.Particularly advantageous derivative or prodrug be when with this compound administration patient Yu, can improve The compounds of this invention bioavailability those materials (for example, make the compound of oral administration be easier to be absorbed into blood), perhaps promote parent compound those materials that transport to biological metabolism compartment (for example, brain or lymphsystem).
" pharmacy acceptable salt " can by any have can shape salifiable functional group, for example The compounds of this invention of acid or alkali functional group preparation.Pharmacy acceptable salt can be derived from the organic or inorganic bronsted lowry acids and bases bronsted lowry.Contain one or more basic functionalities, for example the The compounds of this invention of amino or alkylamino can form pharmacy acceptable salt with pharmaceutically acceptable organic and mineral acid.These salt can be in the last separation and the purge process made acid-stable in situ of The compounds of this invention, perhaps can react respectively and separate formed salt with suitable organic or inorganic acid by The compounds of this invention free alkali form, purifying to prepare.The example of suitable hydrochlorate comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, sulfur hydrogen salt, butyrates, Citrate trianion, camphorate (camphorate), camsilate, cyclopentane propionate, gluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt (glucoheptanoate), glycerophosphate, oxyacetate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmitate, comb shape hydrochlorate (pectinate), peroxydisulfate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecampate.Other acid, for example oxalic acid when itself not accepted by medicine, can use to be suitable as intermediate in order to obtain the salt of The compounds of this invention and its pharmaceutically acceptable acid-adducting salt in preparation.Referring to, " the Pharmaceutical Salts " of Berge etc. for example, J.Pharm.Sci.1977,66:1-19.
The compound of the present invention that contains one or more acidic functionalities can form pharmacy acceptable salt with pharmaceutically acceptable alkali.In these materials, term " pharmacy acceptable salt " refers to inorganic and organic bases adduct nontoxic relatively, compound of the present invention.These salt equally can be in the last separation and the purge process made acid-stable in situ of compound, perhaps can pass through compound free acid form, purifying and suitable alkali, the for example oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate react respectively with ammonia or with pharmaceutically acceptable organic primary, second month in a season or tertiary amine and to prepare.Representational alkaline or alkaline-earth salts comprises lithium, sodium, potassium, calcium, magnesium and aluminium salt etc.The example of more operable alkali comprises sodium hydroxide, potassium hydroxide, bursine, yellow soda ash, N +(C 1- 4Alkyl) 4Deng.The representational organic amine that can be used for forming the alkali adduct comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.The present invention has also predicted any quaternization that contains the group of basic nitrogen of compound disclosed herein.Can obtain water or the molten or dispersible products of oil by this quaternization.Referring to for example, the supra of Berge etc.
The pharmaceutically acceptable prodrug of compound of the present invention includes but not limited to quaternary ammonium derivative, N-Mannich alkali, Schiff alkali, amino acid conjugate pair, phosphoric acid ester, metal-salt and the sulphonate of ester, carbonate, thiocarbonate, N-acyl derivative, N-acyloxy alkyl derivative, tertiary amine.
The compounds of this invention is carried out derivatization include but not limited to the amino replacement of 2-with the appropriate location that produces " prodrug ".Those of ordinary skills understand and need not the over-drastic test and just can finish this derivatization.The various forms of prodrug is as known in the art.For the example of this prodrug derivatives, referring to, for example,
A) Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. etc., Ed.; Academic, 1985,42 volumes, 309-396 page or leaf;
B) Bundgaard, H. " Design and Application of Prodrugs ", A Textbookof Drug Design and Developuaent, Krosgaard-Larsen and H.Bundgaard, Ed., 1991,5 chapters, 113-191 page or leaf; With
c)Bundgaard，H.，Advanced?Drug?Delivery?Review，1992，8，1-38。
Every piece of document all is bonded to herein as a reference.
Term used herein " prodrug " includes but not limited to the combination of following groups and these groups;
The ammonia prodrug:
Figure GSA00000083249100091
The hydroxyl prodrug:
The acyloxy alkyl ester;
Alkoxyl group carbonyl oxygen base alkyl ester;
Alkyl ester;
Aryl ester; With
The ester that contains disulphide.
Term " alkyl " separately or combine refer to have 1～about 30 carbon, more preferably 1～12 carbon, the optional straight chain that replaces or the optional branched saturated hydrocarbon group that replaces.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, tert-pentyl, amyl group, hexyl, heptyl, octyl group etc.Term " cycloalkyl " comprises and comprises monocycle, dicyclo, three rings and the cycloalkyl of high-grade multi-ring alkyl more, and wherein each loop section has 3～about 8 carbon atoms.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc." low alkyl group " is short alkyl, for example contains the alkyl of 1～about 6 carbon atoms.
Term " alkenyl " separately or combine refer to have 1 or a plurality of carbon-to-carbon double bond and have 2～about 30 carbon atoms, more preferably 2～18 carbon, the optional straight chain that replaces or the optional branched hydrocarbyl that replaces.The example of alkenyl comprises vinyl, propenyl, butenyl, 1,3-butadiene base etc.Term " cycloalkenyl group " refers to comprise monocycle, dicyclo, three rings and the cycloalkenyl group of the many cycloalkenyl groups of high-grade more, and wherein each loop section has 3～about 8 carbon atoms." low-grade alkenyl " refers to have the alkenyl of 2～about 6 carbon.
Term " alkynyl " separately or combine refer to have 1 or a plurality of carbon-to-carbon triple bond and have 2～about 30 carbon atoms, more preferably 2～about 12 carbon atoms, 2～about 6 carbon atoms and 2～about 4 carbon atoms, the optional straight chain that replaces or the optional branched hydrocarbyl that replaces.The example of alkynyl comprises ethynyl, 2-propynyl, 2-butyne base, 1,3-diacetylene base etc.Term " cycloalkynyl radical " refers to comprise monocycle, dicyclo, three rings and the cycloalkynyl radical of the many cycloalkynyl radicals of high-grade more, and wherein each each loop section has 3～about 8 carbon atoms." low-grade alkynyl " refers to have the alkynyl of 2～about 6 carbon.
Term " assorted alkyl, heterochain thiazolinyl and assorted alkynyl " comprises alkyl, alkenyl and the alkynyl structure of aforesaid optional replacement, and it has one or more and be selected from non-carbon atom, for example the skeletal chain atom of oxygen, nitrogen, sulphur, phosphorus or its combination.
Term " carbochain " comprises any the be alkyl of straight chain, ring or its combination, alkenyl, alkynyl or assorted alkyl, heterochain thiazolinyl or assorted alkynyl.If described chain comprises one or more rings as a core skeleton part for a part and this link of link, then in order to calculate chain length, described " chain " only comprises the carbon atom at bottom that those constitute given ring or top rather than comprises the two simultaneously, and under the top and the unequal situation of bottom lengths of ring, should adopt the shortest distance to determine chain length.If described chain contains the heteroatoms as the part of skeleton, then those atoms are not calculated as the part of carbon chain lengths.
Term " polynary ring " can comprise any ring texture, comprises aromatic nucleus as described below, hetero-aromatic ring, aliphatic ring, heterocycle and encircles the condensed ring system more.Term " unit " constitutes the quantity of the skeletal atom of ring in order to expression.Therefore, for example pyridine, pyrans and pyrimidine are 6-unit rings, and pyrroles, tetrahydrofuran (THF) and thiophene are 5-unit rings.
Term " aryl " separately or combine the aromatic hydrocarbon group of the optional replacement that refers to 6～about 20 annular atomses, and it comprises single aromatic ring and fused aromatic rings.The fused aromatic rings group contains 2～4 fused rings, and the ring that wherein links together is an aromatic nucleus, is positioned to condense other single ring of intra-annular and can be aromatic nucleus, hetero-aromatic ring, aliphatic series ring or heterocycle.In addition, term aryl comprises list-aromatic ring and the fused aromatic rings that contains 6～about 12 carbon atoms, and those materials that contain 6～about 10 carbon atoms.The example of aryl include but not limited to phenyl, naphthyl, anthryl, Base and benzopyrene basic ring system.Term " lower aryl " refers to have the aryl of 6～about 10 framework ring carbon, for example phenyl and naphthyl ring system.
It is heteroatoms that term " heteroaryl " refers to contain have an appointment 5～about 20 framework ring atoms and wherein one or more annular atomses, for example the aryl of the optional replacement of oxygen, nitrogen, sulphur, selenium and phosphorus.The term heteroaryl comprises list-heteroaryl and the condensed heteroaryl (for example, quinoline, benzothiazole) with at least one heteroatomic optional replacement.Condensed heteroaryl can contain 2～4 fused rings and the ring that links together is a hetero-aromatic ring, and being positioned at other the single ring that condenses ring system can be aromatic nucleus, hetero-aromatic ring, aliphatic series ring or heterocycle.The term heteroaryl also comprises list-heteroaryl or the condensed heteroaryl with 5～about 12 framework ring atoms, and those materials with 5～about 10 framework ring atoms.The example of heteroaryl includes but not limited to furyl, benzofuryl, benzopyranyl, pyridyl, pyrryl, indyl, quinolyl, pyridyl-N-oxide compound, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiazole, benzoglyoxaline, benzoxazole, diazosulfide, Ben Bing oxadiazole, benzotriazole, quinoline, isoquinoline 99.9, indoles, purine radicals, tetrahydro indole base, thienyl etc. and oxide compound thereof.Term " rudimentary heteroaryl " refers to have the heteroaryl of 5～about 10 framework ring atoms, for example pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrryl or furyl.
Term " aliphatic series ring " separately or combine the saturated or unsaturated non-aromatic hydrocarbon ring system of the optional replacement that refers to contain 3～about 20 annular atomses.Term aliphatic series ring comprises list-aliphatic series ring and condenses aliphatic cyclic group.Condense aliphatic ring and can contain 2～4 fused rings, the ring that wherein links together is aliphatic series ring, and be positioned at condense-other single ring of aliphatic cyclic group can be that aromatic nucleus, hetero-aromatic ring, aliphatic series encircle and heterocycle.Term aliphatic series ring also comprises the list-aliphatic series ring that contains 3～about 12 carbon atoms and condenses aliphatic cyclic group, and those materials that contain 3～about 10 carbon atoms.The example of aliphatic series ring includes but not limited to cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclopentyl, ring decyl, cyclo-dodecyl, cyclopentadienyl, indanyl and cyclooctatetraene base (cyclooctatetraenyl) ring system.Term " rudimentary alicyclic radical " refers to have the aliphatic series ring of 3～about 10 framework ring carbon, for example cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclopentyl, decahydro naphthyl and cyclohexyl.
Term " heterocycle " refers to contain the saturated or unsaturated non-aromatic ring group of the optional replacement of 5～about 20 annular atomses, and wherein one or more described annular atomses are heteroatoms, for example oxygen, nitrogen, sulphur and phosphorus.Term aliphatic series ring comprises list-heterocycle and annelated heterocycles group.The annelated heterocycles group can contain 2～4 fused rings, and wherein shack is a heterocycle, and other the single ring that is arranged in the annelated heterocycles group can be aromatic ring, hetero-aromatic ring, aliphatic series ring or heterocycle.The term heterocycle also comprises list-heterocycle and the annelated heterocycles group with 5～about 12 framework ring atoms, and those materials with 5～about 10 framework ring atoms.The heterocyclic example includes but not limited to tetrahydrofuran base, benzodiazepine
Figure GSA00000083249100121
Base, tetrahydrochysene indazole base, dihydroquinoline base etc.Term " rudimentary heterocycle " refers to have the heterocycle system of 5～about 10 framework ring atoms, for example dihydro pyranyl, pyrrolidyl, indyl, piperidyl, piperazinyl etc.
Term " alkylaryl " or " aralkyl " are independent or combine one of them H atom of finger by the aryl of the alkyl substituted above-mentioned definition of above-mentioned definition, for example tolyl, xylyl etc.
Term " aralkyl " is independent or combine one of them H atom of finger by the aryl substiuted alkyl of above-mentioned definition, for example benzyl, 2-phenylethyl etc.
Term " heteroarylalkyl " refers to the alkyl of the above-mentioned definition that one of them H atom has been replaced by the heteroaryl of above-mentioned definition, and each group can be chosen wantonly and be substituted.
Term " alkoxyl group " separately or combine and refer to alkyl ether groups, alkyl-O-, wherein term alkyl such as above-mentioned definition.The example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.
Term " aryloxy " separately or combine and refer to wherein term aryl such as the above-mentioned definition of aryl ethers group.Examples of aryloxy comprises phenoxy group, benzyloxy etc.
Term " alkylthio " separately or combine and refer to alkyl sulfenyl, alkyl-S-, wherein term alkyl such as above-mentioned definition.
Term " arylthio " separately or combine and refer to artyl sulfo, aryl-S-, wherein term aryl such as above-mentioned definition.
Term " heteroarylthio " refers to group heteroaryl-S-, wherein term heteroaryl such as above-mentioned definition.
Term " acyl group " refers to group-C (O) R; wherein R comprises alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, aralkyl or heteroaralkyl, and alkyl wherein, alkenyl, alkynyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical aralkyl or heteroarylalkyl can be chosen wantonly and be substituted.
Term " acyloxy " refers to ester group-OC (O) R, wherein R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, aralkyl or heteroaralkyl, and alkyl wherein, alkenyl, alkynyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, aralkyl or heteroaralkyl can be chosen wantonly and be substituted.
Term " carboxylic ester group " refers to-C (O) OR, and wherein R is alkyl, aryl or aralkyl, and alkyl wherein, aryl and aralkyl are optional to be substituted.
Term " carboxamide groups " refers to
Figure GSA00000083249100131
Wherein, each R and R ' are independently selected from H, alkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, aralkyl and heteroaralkyl, and alkyl wherein, aryl, heteroaryl, alicyclic radical, heterocyclic radical or aralkyl are optional to be substituted.
Term " oxo " refers to=O.
Term " halogen " comprises F, Cl, Br and I.
Term " haloalkyl, halogenated alkenyl, halo alkynyl and halogenated alkoxy " comprises abovementioned alkyl, alkenyl, alkynyl and the alkoxyl group structure that is replaced by one or more fluorine, chlorine, bromine or iodine or its combination.
Term " whole haloalkyl, perhalogeno alkoxyl group and perhalogeno acyl group " refers to abovementioned alkyl, alkoxyl group and the acyl group that all H atoms are all replaced by fluorine, chlorine, bromine or iodine or its combination.
Term " cycloalkyl, aralkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, alkyl, alkynyl, alkenyl, haloalkyl and assorted alkyl " comprises optional cycloalkyl, aralkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, alkyl, alkynyl, alkenyl, haloalkyl and the assorted alkyl that replaces.
Term " alkylamino " refers to group-NHR, and wherein R is independently selected from alkyl.
Term " dialkyl amido " refers to group-NRR ', and wherein R and R ' are alkyl.
Term " sulfide " refers to that sulphur atom is covalently attached on two atoms; The gram formula oxidation state of described sulphur is (II).Term " thioether " can exchange with term " sulfide " and use.
Term " sulfoxide " refer to sulphur atom be covalently attached on three atoms and wherein at least one atom be Sauerstoffatom; The gram formula oxidation state of described sulphur atom is (IV).
Term " sulfone " refer to sulphur atom be covalently attached to four atoms and wherein at least two atoms be Sauerstoffatom; The gram formula oxidation state of described sulphur atom is (VI).
Term " optional " or " randomly " mean subsequently the incident described and situation can but needn't give birth to by beard and hair, and described description comprises situation and nonevent situation that described incident and situation take place.For example, " optional " by the aryl of alkyl list-or two-replace mean described alkyl can but must not exist, perhaps can have an alkyl or have two alkyl, and described description comprises situation that aryl is wherein replaced by one or two alkyl and aryl situation about not replaced by alkyl wherein.
" optional replacement " group can be replacement or unsubstituted.The substituting group of " optional replacement " group can include but not limited to one or more being independently selected from the substituting group of following groups or its specified subclass: low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, heteroaryl, alicyclic radical, heterocyclic radical, aralkyl, heteroaralkyl, lower alkoxy, rudimentary aryloxy, amino, alkylamino, dialkyl amido, alkyl diaryl amino, alkylthio, arylthio, heteroarylthio, oxo, oxa-, carbonyl (C (O)), carboxylic ester group (C (O) OR), carboxamide groups (C (O) NH 2), carboxyl, acyloxy ,-H, halo ,-CN ,-NO 2,-N 3,-SH ,-OH ,-C (O) CH 3, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thienyl, furyl, indoles, indazole, ester, acid amides, phosphonic acid ester, phosphoric acid, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide, thioamides, sulfane base.The optional group that replaces can for replace (for example ,-CH 2CH 3), the full replacement (for example ,-CF 2CF 3), the single replacement (for example ,-CH 2CH 2F) or on full replacement and any level between single the replacement replace (for example ,-CH 2CF 3).
Term " pyridine-1-oxygen base " also refers to " pyridine-N-oxygen base ".
Compounds more of the present invention can contain one or more chiral centres, therefore can have optical siomerism and diastereo-isomerism form.Scope intention of the present invention covers all its isomer, and the mixture of genial trans-isomer(ide), the mixture of diastereomer and the racemic mixture of enantiomer (optical isomer).In addition, can also use known method to separate various forms, and the feature of embodiments more of the present invention may just be the purifying and the enriched fractions of given enantiomer and diastereomer.
" pharmaceutical composition " refers to compound or its pharmacy acceptable salt and other component that one or more are described, the mixture of for example pharmaceutically acceptable carrier and/or excipient herein.The purpose of pharmaceutical composition is in order to help compound to the body administration.
Word used herein " pharmacy acceptable salt " means pharmaceutically acceptable material, composition or carrier, for example liquid or solid filler, thinner, excipient, solvent or packaged material, its participation carry or transport the part of main body medicament from the part of an organ or health to another organ or health.From can be with other composition of preparation compatible and patient is not had on the meaning of infringement, each carrier must be " acceptable ".Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) carbohydrate, for example lactose, dextrose plus saccharose; (2) starch, for example W-Gum and yam starch; (3) Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; (4) Powdered tragacanth gum; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum powder; (8) excipient, for example theobroma oil and suppository wax; (9) oil, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) glycol, for example propylene glycol; (11) polyvalent alcohol, for example glycerine, Sorbitol Powder, N.F,USP MANNITOL and polyoxyethylene glycol; (12) ester class, for example ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent, for example magnesium hydroxide and aluminium hydroxide; (15) Lalgine; (16) do not contain the water of pyrogen thing; (17) isotonic saline solution; (18) Ringer ' s solution; (19) ethanol; (20) phosphate buffer soln; (21) the nontoxic compatible material of other that in pharmaceutical preparation, uses.Physiologically acceptable carrier should be unable to produce serious stimulation to body, and can not eliminate biological activity and form to drug compound.
" excipient " refers to join in the pharmaceutical composition inert substance with further help compound administration.The example of excipient includes but not limited to lime carbonate, calcium phosphate, various carbohydrate and various types of starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
" medicine effective quantity " means the amount that the effect for the treatment of and/or preventing can be provided.Certainly, the compound according to administration of the present invention should comprise that particular compound, route of administration, the illness of treatment and the individuality of treatment of for example administration determined by the particular case relevant with case in order to the concrete dosage that obtains the effect that treats and/or prevents.Per daily dose (single-dose or divided dose administration) commonly used should contain the about 0.01mg/kg of active compound of the present invention～about 50-100mg/kg body weight.Preferred per daily dose should be about 0.05mg/kg～about 20mg/kg usually, it is desirable to about 0.1mg/kg～about 10mg/kg body weight.Also should determine factor, and those of ordinary skills use standard step can determine these factors such as clearance rate, transformation period and maximum permissible limit (MTD).
In the certain methods embodiment, preferred therapeutic action is to suppress the growth that its characteristic is the cell of hyperplasia illness such as mammary cancer to a certain extent.Usually but not necessarily, therapeutic action also should alleviate the one or more symptoms that are different from cell growth or cell mass size to a certain extent.Therapeutic action can comprise, for example following one or more: 1) reduce cell quantity; 2) dwindle the cell size; 3) suppress (that is, slow down to a certain extent, preferably stop) Premeabilisation of cells and enter peripheral organs, for example under the situation of metastasis of cancer; 4) suppress (that is, slow down to a certain extent, preferably stop) metastases; 5) cell growth inhibiting to a certain extent; And/or 6) alleviate the one or more symptoms relevant to a certain extent with illness.
As used in this article, term IC 50Finger in the test of measuring peak response, amount, concentration or the dosage of special test compound when reaching 50% restraining effect of peak response.In some embodiments of the present invention, " the IC of The compounds of this invention 50" value can be greater than the cell that shows the hyperplasia illness, for example breast cancer cell for normal cell.Described value depends on used test.
With the contrast of " standard " expression positive or negative.From the angle negative control of HER2 expression level is for example proteinic owning amount of HER2 and the corresponding sample of normal cell.Negative control can also comprise and not contain the proteinic sample of HER2.On the contrary, positive control contains HER2 protein, and its amount is preferred and in the hyperplasia illness, for example the overexpression of finding in the mammary cancer is corresponding.Contrast can be from fixed or other cell or tissue sample, or contains the part (or not containing part) of purifying.In some embodiments, one or more contrasts can be used as the form of diagnosis " gage ".
With " selectivity target " expression, for example relative with relatively low or normal HER2 level, under the situation of the cell with high HER2 level, for the cell of other type, it influences one type cell with much bigger degree.
II. Compound of the present invention
Compound of the present invention and polymorphic form thereof, solvate, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug demonstrate for the purposes that suppresses HSP90 and treatment and prevention HSP90-dependence disease.
An embodiment of The compounds of this invention is formula A:
Or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
X 1And X 2Identical or different, respectively do for oneself nitrogen or-CR 6
X 3For nitrogen or-CR 3, R wherein 3For hydrogen, OH, keto tautomer ,-OR 8,-CN, halogen, low alkyl group or-C (O) R 9
Work as X 3During for nitrogen, X 4Be nitrogen or group CR 6Work as X 3For-CR 3The time, X 4For-CR 6R 7
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-; With
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical; it is optional separately to be two-or three rings, and optional by H, halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
Condition is:
Described compound is at JP 10025294; US patent 4,748,177; US patent 4,748,177; US patent 6,369,092; WO 00/06573; WO02/055521; WO 02/055082; WO 02/055083; Eur.J.Med.Chem., 1994,29 (1), 3-9; And J.Het.Chem.1990, undiscovered or description in one or more documents of 27 (5), 1409;
-R 4R 5Not the ribose or derivatives thereof, or the sucrose or derivatives thereof;
-R 4R 5Not phosphonic acid ester or phosphonic acids, the perhaps group that replaces of phosphonate ester or phosphonic acids; With
Work as R 4Be (CH 2) n, wherein n=0 or 1 o'clock, R 4And R 5Be not connected with ' O ', for example-CH 2-O-CH 2-or-CH 2-CH 2-O-CH 2-.
In an embodiment of formula A compound, its tautomer, pharmacy acceptable salt or its prodrug, X 1And X 2Identical or different, and respectively do for oneself nitrogen or-CR 6R 1For halogen ,-OR 8,-SR 8Or low alkyl group; R 2For-NR 8R 10R 3For hydrogen ,-OH or keto tautomer ,-OR 8, halogen ,-CN, low alkyl group or-C (O) R 9R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-; And R 5Be alkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, it is optional separately to be two-or three rings, and optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace; R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or OR 11R 11Be low alkyl group or lower aryl; R 10Be hydrogen or low alkyl group.
In an embodiment of formula A compound, its tautomer, pharmacy acceptable salt or its prodrug, R 1Be selected from halogen, hydroxyl, lower alkoxy, rudimentary sulfane base and C 1 - 4Alkyl; And R 2For-NH 2R 3Be hydrogen.
In another embodiment, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment, R 1Be selected from halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1 - 4Alkyl; Randomly, R 2Be NH 2
In another embodiment, R 4For-CH 2-.
In another embodiment, R 4For-(CH 2) n-, n=0～3 wherein, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base and C 1 - 4Alkyl; And R 2Choose wantonly and be-NH 2
In another embodiment, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1 - 4Alkyl; And R 2Choose wantonly and be-NH 2, R 4For-(CH 2) n-, and R 5Be phenyl, benzyl or pyridyl, all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8(or cyclic ethers, for example methylene-dioxy) ,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace; R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11R 11Be low alkyl group or lower aryl; R 10Be hydrogen or low alkyl group.
In another embodiment, R 1Be halogen, R 2For-NH 2, R 4For-CH 2-, R 6Be H or halogen, R 5For choosing wantonly by H, halogen, C 1 - 4Alkyl, C 1 - 4Alkoxyl group, C 1 - 4Alkylthio, whole haloalkyl, perhalogeno alkoxyl group ,-CN ,-NO 2,-NH 2Or-CO 2R 11The phenyl that replaces.
In another embodiment, R 1Be halogen, R 2For-NH 2, R 4For-CH 2-, R 6Be H, R 5For (4-) position is being chosen wantonly by H, halogen, C 1 - 4Alkyl, C 1 - 4Alkoxyl group, C 1 - 4Alkylthio, whole haloalkyl, perhalogeno alkoxyl group ,-CN ,-NO 2,-NH 2Or-CO 2R 11The 2-halo-3 that replaces, the 5-Dimethoxyphenyl.
In another embodiment, R 1Be chlorine, R 2For-NH 2, R 4For-CH 2-, R 6Be H, and R 5Be 2-chloro-3,4, the 5-trimethoxyphenyl.
In another embodiment, R 1Be chlorine, R 2For-NH 2, R 4For-CH 2-, R 6Be H, and R 5Be 2-bromo-3,4, the 5-trimethoxyphenyl.In other embodiments, R 5Be selected from 2-iodo-3,4,5-trimethoxyphenyl, 2-fluoro-3,4,5-trimethoxyphenyl or 2-bromo-3,4,5-trimethoxyphenyl.
Aforementioned arbitrary embodiment can combine under feasible and suitable situation.
On the one hand, the invention provides the compound of formula I:
Figure GSA00000083249100191
Or its tautomer, pharmacy acceptable salt or prodrug, wherein:
X 1And X 2Identical or different, respectively do for oneself nitrogen or-CR 6
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 3For hydrogen, OH or keto tautomer ,-OR 8, halogen ,-CN, low alkyl group or-(CO) R 9
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 6For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-NR 8R 10,-N 3Or-C (O) R 9
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional separately to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 10Be hydrogen or low alkyl group; With
R 11Be low alkyl group or lower aryl.
In an embodiment of formula I compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1 - 4Alkyl; And R 2Be NH 2
In another embodiment of formula I compound or its tautomer, pharmacy acceptable salt or prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula I compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1 - 4Alkyl; And R 2Be NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula I compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2Be NH 2R 4For-CH 2-.
On the other hand, the invention provides the compound of formula IA:
Figure GSA00000083249100211
Or its tautomer, pharmacy acceptable salt or prodrug, wherein:
X 1And X 2Identical or different, and respectively do for oneself nitrogen or group-CR 6
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 6For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-NR 8R 10,-N 3,-CN ,-C (O) R 9, or and R 7Be carbonyl (C=O) together;
R 7Be independently selected from hydrogen, low alkyl group or and R 6Be-C (O) together;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 10Be hydrogen or low alkyl group; With
R 11Be low alkyl group or lower aryl.
In an embodiment of formula IA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2Be NH 2
In another embodiment of formula IA compound or its tautomer, pharmacy acceptable salt or prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula IA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; R 2Be NH 2R 4For-(CH 2) n-, and n=0～3 wherein.
In another embodiment of formula IA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2Be NH 2R 4For-CH 2-.
In one embodiment, the invention provides the compound of formula IB:
Figure GSA00000083249100221
Or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 0Be selected from hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-CN and-NHR 8
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NHR 8
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical and heterocyclic radical, all groups are optional to be substituted, wherein: described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring;
R 8And R 10An optional together ring and an optional 1-3 annular atoms that forms 3-7 annular atoms is the heteroatoms that is selected from O, S and N, and
R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thienyl, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional together ring that forms 3-7 annular atoms, and an optional 1-3 annular atoms is the heteroatoms that is selected from O, S and N;
R 0Or R 3For-OH or-SH, described compound can be used as the mixture of (sulphur) keto tautomer accordingly or keto-enol tautomerism body and exists;
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2Or-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional together ring that forms 3～7 annular atomses, and in the optional annular atoms 1～3 is for being selected from the heteroatoms of O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 11Be low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary heteroaryl or lower aryl; With
R 12Be hydrogen or low alkyl group.
In an embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, aryl, heteroaryl, alicyclic radical or heterocyclic radical respectively do for oneself monocycle or dicyclo.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 0For hydrogen, halogen ,-SH ,-OH or-CN; R 1Be halogen; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9R 3For hydrogen, halogen ,-OR 8,-SR 8,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, lower aryl or rudimentary heteroaryl.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 0For hydrogen, halogen or-CN; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9R 4For-CH 2-.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 0For hydrogen, halogen ,-SH ,-OH or-CN; R 1Be halogen; R 2For-NH 2R 3For hydrogen, halogen ,-OR 8,-SR 8,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, whole haloalkyl, lower aryl or rudimentary heteroaryl, wherein R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2, R 5For having at least 3 substituent phenyl.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2, R 5For having at least 2 substituent pyridyl.
In another embodiment of formula IB compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2, R 5For having at least 2 substituent 1-Oxopyridyls (N-Oxopyridyl).
Another embodiment of the invention is the compound of formula IC:
Figure GSA00000083249100251
Or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 0Be selected from hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-CN or-NHR 8
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NH 2
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2Or-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein work as R 8And R 10Former together form slection becomes the ring of 3～7 annular atomses, and in the optional annular atoms 1～3 for being selected from the heteroatoms of O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10The optional together ring that forms 3～7 annular atomses, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group; With
R 0And R 10The former form slection of linking together becomes optional substituted exocyclic double bond, or optionally forms the ring of 3～7 annular atomses and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N.
In another embodiment of formula IC compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen or low alkyl group; R 4For-CHR 12-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups.
In another embodiment of formula IC compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 0For hydrogen or-NHR 8R 1For halogen ,-OR 11,-SR 11Or low alkyl group; R 10Be hydrogen or low alkyl group.
In another embodiment of formula IC compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 0Be hydrogen; R 1Be halogen; R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; And R 10Be hydrogen.
In another embodiment of formula IC compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 5Be phenyl, pyridyl or 1-Oxopyridyl (N-Oxopyridyl), each R 5Have at least two substituting groups.
Another embodiment of the invention is the compound of formula ID representative:
Figure GSA00000083249100271
Or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NH 2
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical and heterocyclic radical, all groups are optional to be substituted, wherein:
Described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring;
R 8And R 10Linking together optional forms the ring of 3～7 annular atomses and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N, and
R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2Or-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group; With
R 3And R 10Linking together optional forms optional substituted exocyclic double bond, or optionally forms the ring of 3～7 annular atomses and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N.
In an embodiment of formula ID compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 3For hydrogen, halogen ,-OR 8,-SR 8,-NR 8R 10, low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary whole haloalkyl, lower aryl or rudimentary heteroaryl, wherein R 8For hydrogen, low alkyl group, low-grade alkenyl or low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; And R 10Be hydrogen or low alkyl group.
In another embodiment of formula ID compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; And R 10Be hydrogen.
In another embodiment of formula ID compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 3Be hydrogen; R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; And R 10Be hydrogen.
In another embodiment of formula ID compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 5Be phenyl, pyridyl or 1-Oxopyridyl (N-Oxopyridyl) that each group has at least two substituting groups.
Another embodiment of the invention is the compound of formula IE representative:
Figure GSA00000083249100291
Or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NH 2
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, all groups are optional to be substituted, wherein:
Described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring;
R 8And R 10Linking together optional forms the ring of 3～7 annular atomses and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N, and
R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group; With
R 3And R 10Linking together optional forms optional substituted exocyclic double bond, or optionally forms the ring of 3～7 annular atomses and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N.
In an embodiment of formula IE compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 4For-CH 2-; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups.
In another embodiment of formula IE compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 5Be phenyl, pyridyl or 1-Oxopyridyl (N-Oxopyridyl) that each group has at least two substituting groups.
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
The exemplary material of formula IB compound is described in Table I.Can include but not limited to those materials of listing in the above-mentioned definitional part with the prodrug that The compounds of this invention uses.
B. Formula II compound
On the one hand, the invention provides the compound of formula II:
Figure GSA00000083249100311
Or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
X 1And X 2Identical or different, respectively do for oneself nitrogen or-CR 6
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 6For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-NR 8R 10,-N 3,-CN or-C (O) R 9
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 10Be hydrogen or low alkyl group; With
R 11Be low alkyl group or lower aryl.
In an embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen; R 2For-NH 2R 4For-CH 2-.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 4For-CH 2-; R 5Be phenyl, benzyl or pyridyl, and optional independently by H, halogen, low alkyl group ,-SR 8,-OR 8(or cyclic ethers, for example methylene-dioxy) ,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace; R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11R 11Be low alkyl group or lower aryl; And R 10Be hydrogen or low alkyl group.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen; R 2For-NH 2R 4For-CH 2-; R 6Be hydrogen or halogen; R 5For choosing wantonly by H, halogen, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkylthio, whole haloalkyl, perhalogeno alkoxyl group ,-CN ,-NO 2,-NH 2Or-CO 2R 11The phenyl that replaces.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen; R 2For-NH 2R 4For-CH 2-; R 6Be H; R wherein 5For on to (4-) position, choosing wantonly by H, halogen, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkylthio, whole haloalkyl, perhalogeno alkoxyl group ,-CN ,-NO 2,-NH 2Or-CO 2R 11The 2-halo-3 that replaces, the 5-Dimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be H; And R 5Be 2-chloro-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be H; And R 5Be 2-bromo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be H; And R 5Be 2-iodo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be H; And R 5Be 2-fluoro-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be H, and R 5Be 2-bromo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be H, and R 5Be 2-iodo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be H and R 5Be 2-iodo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be H and R 5Be 2-fluoro-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be halo, and R 5Be 2-chloro-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be chlorine; R 2For-NH 2R 4For-CH 2-; R 6Be halo, and R 5Be 2-bromo-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be halo, and R 5Be 2-chloro-3,4, the 5-trimethoxyphenyl.
In another embodiment of formula II compound or its tautomer, pharmacy acceptable salt or its prodrug, R 1Be bromine; R 2For-NH 2R 4For-CH 2-; R 6Be halo and R 5Be 2-bromo-3,4, the 5-trimethoxyphenyl.
In one embodiment, the invention provides the compound of formula IIA:
Figure GSA00000083249100341
Or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 6For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-NR 8R 10,-N 3,-CN or-C (O) R 9
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 10Be hydrogen or low alkyl group; With
R 11Be low alkyl group or lower aryl.
In an embodiment of formula IIA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2Be NH 2
In another embodiment of formula IIA compound or its tautomer, pharmacy acceptable salt or prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula IIA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2Be NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula IIA compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2Be NH 2R 4For-CH 2-.
In one embodiment, the invention provides the compound of formula IIB:
Figure GSA00000083249100351
Wherein:
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 6For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-NR 8R 10,-N 3,-CN or-C (O) R 9
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 10Be hydrogen or low alkyl group; With
R 11Be low alkyl group or lower aryl.
In an embodiment of formula IIB compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2Be NH 2
In another embodiment of formula IIB compound or its tautomer, pharmacy acceptable salt or prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula IIB compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2Be NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula IIB compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2Be NH 2R 4For-CH 2-.
In one embodiment, the invention provides the compound of formula IIC:
Figure GSA00000083249100361
Wherein:
R 1Be halogen or low alkyl group;
R 2For-NR 8R 10
R 4For-CHR 12-;
R 3Be hydrogen, halogen or CN;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups, and wherein when described heteroaryl was only replaced by 2 substituting groups, described two substituting groups must form the part of the optional fused rings that replaces,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-C (O) R 9,-NO 2Or-NR 8R 10, phosphonic acid ester and phosphonic acids;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11
R 10Be hydrogen or low alkyl group independently;
R 11Be low alkyl group, lower aryl or rudimentary heteroaryl;
R 12Be hydrogen or low alkyl group;
Condition is
Work as R 5During for aryl, R 5It is not the organic-metallic cyclopentadiene;
Work as R 5During for phenyl, substituting group is not 3,5 two-halos;
Work as R 5During for alicyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon;
Work as R 5During for heterocyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon, or ring system is not the tetramethyleneimine of four-replacement.
In another embodiment, the invention provides the compound of formula IID, it is R wherein 4For-CH 2-formula IIC compound:
Or its polymorphic form, solvate, ester, tautomer, enantiomer, diastereomer, pharmacy acceptable salt or prodrug, wherein:
R 1Be halogen or low alkyl group;
R 2For-NR 8R 10
R 3For hydrogen, halogen or-CN;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups, and wherein when described heteroaryl was only replaced by 2 substituting groups, described two substituting groups must form the part of the optional fused rings that replaces,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-C (O) R 9,-NO 2Or-NR 8R 10, phosphonic acid ester and phosphonic acids;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11
R 10Be hydrogen or low alkyl group independently;
R 11Be low alkyl group, lower aryl or rudimentary heteroaryl;
R 12Be hydrogen or low alkyl group;
Condition is
Work as R 5During for aryl, R 5It is not the organic-metallic cyclopentadiene;
Work as R 5During for phenyl, substituting group is not 3,5 two-halos;
Work as R 5During for alicyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon;
Work as R 5During for heterocyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon, or ring system is not the tetramethyleneimine of four-replacement.
In an embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen or methyl; And R 2For-NHR 8, R wherein 8For hydrogen or-C (O) R 9
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 2For-NH 2And R 3Be hydrogen.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2For-NH 2R 3Be hydrogen; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo, described aryl is replaced by 4～5 substituting groups, described heteroaryl is replaced by 2～5 substituting groups, wherein when described heteroaryl was only replaced by 2 substituting groups, described 2 substituting groups must form the part of the optional fused rings that replaces.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent phenyl.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent pyridyl.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent 1-Oxopyridyls (N-Oxopyridyl).
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, aryl, heteroaryl, alicyclic radical or heterocyclic radical respectively do for oneself monocycle or dicyclo.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen or methyl; And R 2For-NHR 8, R wherein 8For hydrogen or-C (O) R 9
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R wherein 1Be halogen.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R wherein 2For-NH 2And R 3Be hydrogen.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2For-NH 2R 3Be hydrogen; R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo, described aryl is replaced by 4～5 substituting groups, described heteroaryl is replaced by 2～5 substituting groups, wherein when described heteroaryl was only replaced by 2 substituting groups, described 2 substituting groups must form the part of the optional fused rings that replaces.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent phenyl.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent pyridyl.
In another embodiment of formula IID compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 2For-NH 2And R 5For having 3～5 substituent 1-Oxopyridyls (N-Oxopyridyl).
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
In another embodiment, the invention provides compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug according to following method preparation, described method comprises:
Make the compound reaction of compound and the formula Z of formula Y, wherein
Y as shown in the formula arbitrary structural formula shown in:
Figure GSA00000083249100401
Z is L 1-R 4-R 5Wherein:
L 1For halogen ,-NR 8R 10, trifluoromethanesulfonic acid root, tosylate or methanesulfonate;
R 4For-CHR 12-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein:
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups, and wherein when described heteroaryl was only replaced by 2 substituting groups, described two substituting groups must form the part of the optional fused rings that replaces,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-C (O) R 9,-NO 2Or-NR 8R 10, phosphonic acid ester and phosphonic acids;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11
R 10Be hydrogen or low alkyl group independently;
R 11Be low alkyl group, lower aryl or rudimentary heteroaryl;
R 12Be hydrogen or low alkyl group independently;
R 21For halogen, low alkyl group or-OH;
R 22For-NR 8R 10
R 23For hydrogen, halogen or-CN;
R 24For-NH 2,-NO 2Or-NO;
R 25For halogen or-OH;
R 26For-C (O) NH 2Or C (O) OEt; With
R 27For-NH 2,-OH or halogen;
Condition is
Work as R 5During for aryl, R 5It is not the organic-metallic cyclopentadiene;
Work as R 5During for phenyl, substituting group is not 3,5 two-halos;
Work as R 5During for alicyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon;
Work as R 5During for heterocyclic radical, ring system does not contain the sp of any four-replacement 3Ring carbon, or ring system is not the tetramethyleneimine of four-replacement.
In an embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, it is optional to be single-or dicyclo.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 4For-CH 2-.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, L 1For-Cl ,-Br or-NH 2R 5Be aryl or heteroaryl, wherein said aryl is replaced by 4～5 substituting groups.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, the purine of Y for replacing.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent carried out, and described solvent comprises a kind of material that is selected from DMF, THF and DMSO.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent that comprises DMF carried out.
The compound that is used for the treatment of in the method is the HSP90 inhibitor of Formula Il C compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug,
Figure GSA00000083249100421
Wherein:
R 1For halogen ,-OR 11,-SR 11,-NHR 8, hydrogen or low alkyl group;
R 2For-NR 8R 10
R 3For hydrogen, halogen ,-N 3Or-CN;
R 4For-(CHR 12) n-, n=0,1 or 2 wherein;-C (O) ,-C (S) or-S (O)-;
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups optional by halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-C (O) R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11
R 10Be hydrogen or low alkyl group independently;
R 11Be low alkyl group, lower aryl or rudimentary heteroaryl;
R 12Be hydrogen or low alkyl group;
Condition is
-R 4R 5Be not the ribose or derivatives thereof, or the sucrose or derivatives thereof;
-R 4R 5Be not phosphonic acid ester or phosphonic acids, or phosphonate ester or phosphonic acids replacement; With
Work as R 4For-(CH 12) n-, wherein n=1 or 2 o'clock, then R 4And R 5Do not connect by ehter bond.
At an embodiment of the formula IIC compound that is used for the inventive method, R 3For hydrogen, halogen or-CN; R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups optional by halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary alicyclic radical, aralkyl, aryloxy, aryloxy alkyl, alkoxyalkyl, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group ,-N 3,-SR 8,-OR 8,-CN ,-C (O) R 9,-NO 2Or-NR 8R 10, phosphonic acid ester or phosphonic acids replace;
At another embodiment of the formula IIC compound that is used for the inventive method or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen or methyl, and R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9
At another embodiment of the formula IIC compound that is used for the inventive method, R 2For-NH 2, and R 3Be hydrogen.
At another embodiment of the formula IIC compound that is used for the inventive method, R 4For-CH 2-.
At another embodiment of the formula IIC compound that is used for the inventive method, wherein R 1Be halogen; R 2For-NH 2R 3Be hydrogen; R 4For-CH 2-; R 5Be aryl and heteroaryl, described aryl and heteroaryl are monocycle or dicyclo, described aryl is replaced by 4～5 substituting groups, described heteroaryl is replaced by 2～5 substituting groups, wherein when described heteroaryl was only replaced by 2 substituting groups, described 2 substituting groups must form the part of the optional fused rings that replaces.
At another embodiment of the formula IIC compound that is used for the inventive method, R 1Be chlorine or bromine, R 2For-NH 2, and R 5For having 3～5 substituent phenyl.
At another embodiment of the formula IIC compound that is used for the inventive method, R 1Be chlorine or bromine, R 2For-NH 2, and R 5For having 3～5 substituent pyridyl.
At another embodiment of the formula IIC compound that is used for the inventive method, R 1Be chlorine or bromine, R 2For-NH 2, and R 5For having 3～5 substituent 1-Oxopyridyls (N-Oxopyridyl).
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
Has exemplary material described in Table II based on the The compounds of this invention of following formula IIC.Operable suitable prodrug according to described compound includes but not limited to those listed in definitional part materials.
C. The formula III compound
On the one hand, the invention provides the compound of formula III:
Figure GSA00000083249100441
Or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein
X 1And X 2Identical or different, respectively do for oneself nitrogen or-CR 6
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 3For hydrogen ,-OH or keto tautomer ,-OR 8, halogen ,-CN, low alkyl group or-C (O) R 9
R 4For-(CH 2) n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 5Be alkyl, aryl, heteroaryl, alicyclic radical, heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 11Be low alkyl group or lower aryl; With
R 10Be hydrogen or low alkyl group.
In an embodiment of formula III compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2
In another embodiment of formula III compound or its tautomer, pharmacy acceptable salt or prodrug, R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula III compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In another embodiment of formula III compound or its tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2For-NH 2And R 4For-CH 2-.
A compound that embodiment is formula III A based on the formula III compound:
Figure GSA00000083249100451
Or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NHR 8
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-(CO) R 9,-CO 2H, NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical and heterocyclic radical, all groups are optional to be substituted, wherein:
Described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring;
R 8And R 10Linking together optional forms the ring of 3～7 annular atomses and 1～2 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N, and R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, lower aryl, rudimentary heteroaryl, rudimentary alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl; With
R 12Be hydrogen or low alkyl group.
In an embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen or low alkyl group; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9R 5Be aryl or heterocyclic radical, described aryl or heteroaryl respectively do for oneself monocycle or dicyclo.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 2For-NH 2R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, lower aryl, lower aryl, rudimentary alicyclic radical or rudimentary heterocyclic radical, R 9Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl, and R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N; And R 5Be aryl or heterocyclic radical, described aryl or heteroaryl respectively do for oneself monocycle or dicyclo.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen or low alkyl group; R 2For-NH 2R 4For-(CH 2)-; R 5Be aryl, heterocyclic radical, alicyclic radical or heterocyclic radical, described aryl, heteroaryl, alicyclic radical or heterocyclic radical respectively do for oneself monocycle or dicyclo.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2For-NH 2R 3For hydrogen, halogen ,-SR 8,-OR 8, low alkyl group, lower aryl, rudimentary heteroaryl or-NR 8R 10, R 8And R 10The optional ring that forms 3～7 annular atomses that links together, and randomly 1～3 atom in the annular atoms is the heteroatoms that is selected from O, S and N; R 4For-(CH 2)-; R 5Be aryl or heterocyclic radical, wherein said aryl or heteroaryl respectively do for oneself monocycle or dicyclo.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, and R 5For having 3～5 substituent phenyl.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, and R 5For having 3～5 substituent pyridyl.
In another embodiment of formula III A compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, and R 5For having 3～5 substituent 1-Oxopyridyls (N-Oxopyridyl).
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
Other embodiment based on the formula III compound is the compound of formula III B:
Figure GSA00000083249100481
Or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NHR 8
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl; With
R 12Be hydrogen or low alkyl group; With
R 15Be hydrogen, low alkyl group, low-grade alkenyl or low-grade alkynyl.
In an embodiment of formula III B compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9R 5Be aryl, heterocyclic radical or heterocyclic radical, all groups optional for single-, two-or three-ring; And R 9Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl.
In another embodiment of formula III B compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 1Be halogen or low alkyl group; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9R 5Be aryl, heterocyclic radical, alicyclic radical or heterocyclic radical, all groups optional for single-, two-or three-ring.
In another embodiment of formula III B compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 2For-NH 2R 5For having 3～5 substituent phenyl.
In another embodiment of formula III B compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 2For-NH 2R 5For having 3～5 substituent pyridyl.
In another embodiment of formula III B compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R wherein 1Be chlorine or bromine; R 2For-NH 2R 5For having 3～5 substituent 1-Oxopyridyls (N-Oxopyridyl).
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
Other embodiment based on the formula III compound is that described method comprises according to compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or the prodrug of following method preparation:
Make the compound reaction of compound and the formula Z of formula Y, wherein:
Y as shown in the formula arbitrary structural formula shown in:
Figure GSA00000083249100501
Z is L 1-R 4-R 5Wherein:
L 1For halogen ,-NR 8R 10, trifluoromethanesulfonic acid root, tosylate or methanesulfonate;
R 4For-(CHR 12)-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional ring that forms 3～7 annular atomses that links together, and randomly 1～3 atom in the annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 12Be hydrogen or low alkyl group;
R 21For halogen ,-OR 8,-SR 8Or low alkyl group;
R 22For-NR 8R 10
R 23For hydrogen ,-OH or its keto tautomer ,-OR 8, halogen ,-CN, low alkyl group, lower aryl or-(CO) R 9
R 24For-CHO ,-NH 2,-NO 2Or-NO;
R 25For halogen or-OH;
R 26For-C (O) NH 2Or C (O) OEt; With
R 27For-NH 2,-OH or halogen;
In an embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, it is optional to be single-or dicyclo.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, L 1For-Cl ,-Br or-NH 2R 4For-CH 2-; And R 5Be aryl or heteroaryl.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, Y is a pyrazolopyrimidine.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent carried out, and described solvent comprises a kind of material that is selected from DMF, THF and DMSO.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent that comprises DMF carried out.
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
Based on formula III A, wherein R 2=-NH 2The exemplary material of The compounds of this invention in Table III, be described.Operable suitable prodrug according to those compounds includes but not limited to those listed in definitional part materials.
D. Formula IV compound
On the other hand, the invention provides the compound of formula IV:
Figure GSA00000083249100521
Or its polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt or prodrug, wherein
X 1And X 2Identical or different, and respectively do for oneself nitrogen or-CR 6
R 1For halogen ,-OR 8,-SR 8Or low alkyl group;
R 2For-NR 8R 10
R 4For-CH 2n-, wherein n=0～3 ,-C (O) ,-C (S) ,-SO 2-or-SO 2N-;
R 5Be alkyl, aryl, heteroaryl, alicyclic radical or heterocyclic radical, all groups are optional to be two-or three rings, and all groups optional by H, halogen, low alkyl group ,-SR 8,-OR 8,-CN ,-CO 2R 9,-NO 2Or-NR 8R 10Replace;
R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 8R 10Or-OR 11
R 11Be low alkyl group or lower aryl; With
R 10Be hydrogen or low alkyl group.
In an embodiment of formula IV compound, its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2
In an embodiment of formula IV compound, its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2R 4For-CH 2-,-C (O) ,-C (S) ,-SO 2-.
In an embodiment of formula IV compound, its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen or C 1-4Alkyl; And R 2For-NH 2R 4For-CH 2-.
In an embodiment of formula IV compound, its tautomer, pharmacy acceptable salt or its prodrug, R 1Be halogen, hydroxyl, lower alkoxy, rudimentary sulfane base or C 1-4Alkyl; And R 2For-NH 2R 4For-(CH 2) n-, n=0～3 wherein.
In an embodiment of formula IV compound, its tautomer, pharmacy acceptable salt or its prodrug, R 4For-C (O) ,-CH 2-; R 1Be halogen, lower alkoxy or C 1-4Alkyl; And R 2For-NH 2
An embodiment based on formula IV compound is a formula IVA compound:
Figure GSA00000083249100531
Or its polymorphic form, solvate, ester, tautomer, enantiomer, diastereomer, pharmacy acceptable salt or prodrug, wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NHR 8
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein:
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary heteroaryl or lower aryl; And R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-; With
R 12Be hydrogen or low alkyl group;
Condition is to work as R 5During for alicyclic radical, described ring system does not contain the sp of any four-replacement 3Ring carbon.
In an embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, diastereomer, pharmacy acceptable salt or prodrug, aryl, heteroaryl, alicyclic radical or heterocyclic radical respectively do for oneself monocycle or dicyclo.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, diastereomer, pharmacy acceptable salt or prodrug, R 1Be halogen; And R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine; R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9And R 4Be low alkyl group.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 2For-NHR 8, R wherein 8For hydrogen or-(CO) R 9And R 4For-CH 2-.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be halogen; R 2For-NH 2R 4For-CH 2-; And R 5Be aryl or heteroaryl, wherein said aryl and heteroaryl respectively do for oneself monocycle or dicyclo and replaced by 3～5 substituting groups.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, R 2For-NH 2And R 5For having at least 3 substituent phenyl.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, R 2For-NH 2And R 5For having at least 2 substituent pyridyl.
In another embodiment of formula IVA compound or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, R 1Be chlorine or bromine, R 2For-NH 2And R 5For having at least 2 substituent 1-Oxopyridyls (N-Oxopyridyl).
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
In another embodiment, the invention provides compound or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug according to following method preparation, described method comprises:
Make the compound reaction of compound and the formula Z of formula Y, wherein:
Y as shown in the formula arbitrary structural formula shown in:
Figure GSA00000083249100551
Z is L 1-R 4-R 5Wherein:
L 1For halogen ,-NR 8R 10, trifluoromethanesulfonic acid root, tosylate or methanesulfonate;
R 4For-CHR 12-,-C (O) ,-C (S) ,-S (O)-or-SO 2-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2With-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional ring that forms 3～7 annular atomses that links together, and randomly 1～3 atom in the annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl or low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, low-grade alkenyl or low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and 1～3 atom in the optional annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl or low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group;
R 21For halogen ,-OR 8,-SR 8Or low alkyl group;
R 22For-NR 8R 10
R 24For-NH 2,-NO 2Or-NO;
R 25For halogen or-OH;
R 26For-C (O) NH 2Or C (O) OEt; With
R 27For-NH 2,-OH or halogen;
Condition is to work as R 5During for alicyclic radical, described ring system does not contain the sp of any four-replacement 3Ring carbon.
In an embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, L 1For-Cl ,-Br or-NH 2R 5Be aryl or heteroaryl.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 4For-CH 2-.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, it is optional to be single-or dicyclo.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, L 1For-Cl ,-Br or-NH 2R 4For-CH 2-; And R 5Be aryl or heteroaryl.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, Y is a triazolo pyrimidine.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, Y is a triazole.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, Y is a pyrimidine.
In another embodiment of the compound for preparing by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent carried out, and described solvent comprises a kind of material that is selected from DMF, THF and DMSO.
In another embodiment of the compound that is prepared by method of the present invention or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug, described being reflected in the solvent that comprises DMF carried out.
Should be appreciated that aforementioned arbitrary embodiment can combine under feasible and suitable situation.
Exemplary material based on the The compounds of this invention of formula IVA is described in table 4.Operable prodrug according to these compounds includes but not limited to those listed in definitional part materials.
Table I: based on the example compound of formula IA
Figure GSA00000083249100582
Figure GSA00000083249100601
Figure GSA00000083249100611
Figure GSA00000083249100621
Figure GSA00000083249100631
Figure GSA00000083249100641
Figure GSA00000083249100651
Figure GSA00000083249100661
Figure GSA00000083249100681
Figure GSA00000083249100691
Figure GSA00000083249100701
Figure GSA00000083249100711
Figure GSA00000083249100721
Figure GSA00000083249100741
Figure GSA00000083249100751
Figure GSA00000083249100761
Figure GSA00000083249100791
Figure GSA00000083249100801
Figure GSA00000083249100811
Figure GSA00000083249100821
Figure GSA00000083249100831
Figure GSA00000083249100841
Figure GSA00000083249100851
Figure GSA00000083249100861
Figure GSA00000083249100871
Figure GSA00000083249100881
Figure GSA00000083249100891
Figure GSA00000083249100901
Figure GSA00000083249100911
Figure GSA00000083249100921
Figure GSA00000083249100931
Figure GSA00000083249100941
Figure GSA00000083249100951
Figure GSA00000083249100961
Figure GSA00000083249100971
Figure GSA00000083249100981
Figure GSA00000083249100991
Figure GSA00000083249101001
Figure GSA00000083249101011
Figure GSA00000083249101021
Figure GSA00000083249101031
Figure GSA00000083249101041
Figure GSA00000083249101051
Figure GSA00000083249101061
Compound useful in the table 1 is: 2,3,17,18,27,28,62,63,77,78,92,93,129,130,238,239,242,243,245,246,247,248,249,250,251,252,253,267,268,287,288,291,292,293,294,295,296,297,298,312,313,332,333,334,335,336,337,338,339,351,352,365,366,384,385,398,399,400,401,402,403,404,405,417,418,431,432,433,434,435,436,437,438,450,451,464,465,483,484,497,498,530,531,549,550,562,563,574,575,577,578,589,590,592,593,604,605,607,608,619,620,755,756,759,760,761,762,763,764,765,766,780,781,800,801,804,805,806,807,808,809,810,811,825,826,845,846,863,864,865,866,875 and 876 (what therefrom select is 17,18,27,28,62,63,77,78,242,243,245,246,247,248,249,250,251,252,253,267,268,287,288,291,292,293,294,295,296,312,313,431,432,755,756,759,760,761,762,763,764,800 and 801.
The example compound of table 2. formula IIC of the present invention
Figure GSA00000083249101062
No.? Embodiment R 1 R 3 R 4 R 5
1? 48? Cl? H? CH 2 3,4, the 5-trimethoxyphenyl
2? 98? Cl? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
3? 51? Cl? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
4? 106? Cl? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
5? ? Cl? H? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
6? ? Cl? H? CH 2 3,4, the 5-trimethylphenyl
7? ? Cl? H? CH 2 2-chloro-3,4, the 5-trimethylphenyl
8? ? Cl? H? CH 2 2-bromo-3,4, the 5-trimethylphenyl
9? ? Cl? H? CH 2 2-iodo-3,4, the 5-trimethylphenyl
10? ? Cl? H? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
11? 43? Cl? H? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
12? ? Cl? H? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
13? 44? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
14? ? Cl? H? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
15? ? Cl? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
16? ? Cl? H? CH 2 3,5-two chloro-4-aminomethyl phenyls
17? ? Cl? H? CH 2 2,3,5-three chloro-4-aminomethyl phenyls
18? ? Cl? H? CH 2 2-bromo-3,5-two chloro-4-aminomethyl phenyls
19? ? Cl? H? CH 2 2-iodo-3,5-two chloro-4-aminomethyl phenyls
20? ? Cl? H? CH 2 2-fluoro-3,5-two chloro-4-aminomethyl phenyls
21? ? Cl? H? CH 2 3,5-two bromo-4-aminomethyl phenyls
22? ? Cl? H? CH 2 2-chloro-3,5-two bromo-4-aminomethyl phenyls
23? ? Cl? H? CH 2 2,3,5-three bromo-4-methyl phenyl phenyls
24? ? Cl? H? CH 2 2-iodo-3,5-two bromo-4-aminomethyl phenyls
25? ? Cl? H? CH 2 2-fluoro-3,5-two bromo-4-aminomethyl phenyls
26? ? Cl? H? CH 2 3,5-two chloro-4-p-methoxy-phenyls
27? ? Cl? H? CH 2 2,3,5-three chloro-4-p-methoxy-phenyls
28? ? Cl? H? CH 2 2-bromo-3,5-two chloro-4-p-methoxy-phenyls
29? ? Cl? H? CH 2 2-iodo-3,5-two chloro-4-p-methoxy-phenyls
30? ? Cl? H? CH 2 2-fluoro-3,5-two chloro-4-p-methoxy-phenyls
31? ? Cl? H? CH 2 3,5-two bromo-4-p-methoxy-phenyls
32? ? Cl? H? CH 2 2-chloro-3,5-two bromo-4-p-methoxy-phenyls
33? ? Cl? H? CH 2 2,3,5-three bromo-4-p-methoxy-phenyls
34? ? Cl? H? CH 2 2-iodo-3,5-two bromo-4-p-methoxy-phenyls
35? ? Cl? H? CH 2 2-fluoro-3,5-two bromo-4-p-methoxy-phenyls
36? ? Cl? H? CH 2 3-chloro-5-bromo-4-aminomethyl phenyl
37? ? Cl? H? CH 2 2,3-two chloro-5-bromo-4-aminomethyl phenyls
38? ? Cl? H? CH 2 2,5-two bromo-3-chloro-4-aminomethyl phenyls
39? ? Cl? H? CH 2 2-iodo-3-chloro-5-bromo-4-aminomethyl phenyl
40? ? Cl? H? CH 2 2-fluoro-3-chloro-5-bromo-4-aminomethyl phenyl
41? ? Cl? H? CH 2 3-chloro-5-bromo-4-p-methoxy-phenyl phenyl
42? ? Cl? H? CH 2 2,3-two chloro-5-bromo-4-p-methoxy-phenyls
43? ? Cl? H? CH 2 2,5-two bromo-3-chloro-4-p-methoxy-phenyls
44? ? Cl? H? CH 2 2-iodo-3-chloro-5-bromo-4-p-methoxy-phenyl
45? ? Cl? H? CH 2 2-fluoro-3-chloro-5-bromo-4-p-methoxy-phenyl
46? ? Cl? H? CH 2 3-bromo-5-chloro-4-aminomethyl phenyl
47? ? Cl? H? CH 2 2,5-two chloro-3-bromo-4-aminomethyl phenyls
48? ? Cl? H? CH 2 2,3-two bromo-5-chloro-4-aminomethyl phenyls
49? ? Cl? H? CH 2 2-iodo-3-bromo-5-chloro-4-aminomethyl phenyl
50? ? Cl? H? CH 2 2-fluoro-3-bromo-5-chloro-4-aminomethyl phenyl
51? ? Cl? H? CH 2 3-bromo-5-chloro-4-p-methoxy-phenyl
52? ? Cl? H? CH 2 2,5-two chloro-3-bromo-4-p-methoxy-phenyls
53? ? Cl? H? CH 2 2,3-two bromo-5-chloro-4-p-methoxy-phenyls
54? ? Cl? H? CH 2 2-iodo-3-bromo-5-chloro-4-p-methoxy-phenyl
55? ? Cl? H? CH 2 2-fluoro-3-bromo-5-chloro-4-p-methoxy-phenyl
56? ? Cl? H? CH 2 3,5-dimethoxy-4 '-trifluoromethyl
57? ? Cl? H? CH 2 2-chloro-3,5-dimethoxy-4 '-trifluoromethyl
58? ? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-trifluoromethyl
59? ? Cl? H? CH 2 2-iodo-3,5-dimethoxy-4 '-trifluoromethyl
? ? ? ? ? Phenyl
60? ? Cl? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-trifluoromethyl
61? ? Cl? H? CH 2 3,5-two bromo-4-Trifluoromethoxyphen-ls
62? ? Cl? H? CH 2 2-chloro-3,5-two bromo-4-Trifluoromethoxyphen-ls
63? ? Cl? H? CH 2 2,3,5-three bromo-4-Trifluoromethoxyphen-ls
64? ? Cl? H? CH 2 2-iodo-3,5-two bromo-4-Trifluoromethoxyphen-ls
65? ? Cl? H? CH 2 2-fluoro-3,5-two bromo-4-Trifluoromethoxyphen-ls
66? ? Cl? H? CH 2 3,5-dimethyl-4-p-methoxy-phenyl
67? ? Cl? H? CH 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
68? ? Cl? H? CH 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
69? ? Cl? H? CH 2 2-iodo-3,5-dimethyl-4-p-methoxy-phenyl
70? ? Cl? H? CH 2 2-fluoro-3,5-dimethyl-4-p-methoxy-phenyl
71? ? Cl? H? CH 2 3,5-dimethyl-4-bromophenyl
72? ? Cl? H? CH 2 2-chloro-3,5-dimethyl-4-bromophenyl
73? ? Cl? H? CH 2 2,4-two bromo-3,5-3,5-dimethylphenyl
74? ? Cl? H? CH 2 2-iodo-3,5-dimethyl-4-bromophenyl
75? ? Cl? H? CH 2 2-fluoro-3,5-dimethyl-4-bromophenyl
76? ? Cl? H? CH 2 3,5-dimethyl-4-chloro-phenyl-
77? ? Cl? H? CH 2 2,4-two chloro-3,5-3,5-dimethylphenyl
78? ? Cl? H? CH 2 2-bromo-3,5-dimethyl-4-chloro-phenyl-
79? ? Cl? H? CH 2 2-iodo-3,5-dimethyl-4-chloro-phenyl-
80? ? Cl? H? CH 2 2-fluoro-3,5-dimethyl-4-chloro-phenyl-
81? 101? Br? H? CH 2 3,4, the 5-trimethoxyphenyl
82? 77? Br? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
83? 102? Br? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
84? ? Br? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
85? ? Br? H? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
86? ? Br? H? CH 2 3,4, the 5-trimethylphenyl
87? ? Br? H? CH 2 2-chloro-3,4, the 5-trimethylphenyl
88? ? Br? H? CH 2 2-bromo-3,4, the 5-trimethylphenyl
89? ? Br? H? CH 2 2-iodo-3,4, the 5-trimethylphenyl
90? ? Br? H? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
91? ? Br? H? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
92? ? Br? H? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
93? ? Br? H? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
94? ? Br? H? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
95? ? Br? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
96? ? Br? H? CH 2 3,5-two chloro-4-aminomethyl phenyls
97? ? Br? H? CH 2 2,3,5-three chloro-4-aminomethyl phenyls
98? ? Br? H? CH 2 2-bromo-3,5-two chloro-4-aminomethyl phenyls
99? ? Br? H? CH 2 2-iodo-3,5-two chloro-4-aminomethyl phenyls
100? ? Br? H? CH 2 2-fluoro-3,5-two chloro-4-aminomethyl phenyls
101? ? Br? H? CH 2 3,5-two bromo-4-aminomethyl phenyls
102? ? Br? H? CH 2 2-chloro-3,5-two bromo-4-aminomethyl phenyls
103? ? Br? H? CH 2 2,3,5-three bromo-4-methyl phenyl phenyls
104? ? Br? H? CH 2 2-iodo-3,5-two bromo-4-aminomethyl phenyls
105? ? Br? H? CH 2 2-fluoro-3,5-two bromo-4-aminomethyl phenyls
106? ? Br? H? CH 2 3,5-two chloro-4-p-methoxy-phenyls
107? ? Br? H? CH 2 2,3,5-three chloro-4-p-methoxy-phenyls
108? ? Br? H? CH 2 2-bromo-3,5-two chloro-4-p-methoxy-phenyls
109? ? Br? H? CH 2 2-iodo-3,5-two chloro-4-p-methoxy-phenyls
110? ? Br? H? CH 2 2-fluoro-3,5-two chloro-4-p-methoxy-phenyls
111? ? Br? H? CH 2 3,5-two bromo-4-p-methoxy-phenyls
112? ? Br? H? CH 2 2-chloro-3,5-two bromo-4-p-methoxy-phenyls
113? ? Br? H? CH 2 2,3,5-three bromo-4-p-methoxy-phenyls
114? ? Br? H? CH 2 2-iodo-3,5-two bromo-4-p-methoxy-phenyls
115? ? Br? H? CH 2 2-fluoro-3,5-two bromo-4-p-methoxy-phenyls
116? ? Br? H? CH 2 3-chloro-5-bromo-4-aminomethyl phenyl
117? ? Br? H? CH 2 2,3-two chloro-5-bromo-4-aminomethyl phenyls
118? ? Br? H? CH 2 2,5-two bromo-3-chloro-4-aminomethyl phenyls
119? ? Br? H? CH 2 2-iodo-3-chloro-5-bromo-4-aminomethyl phenyl
120? ? Br? H? CH 2 2-fluoro-3-chloro-5-bromo-4-aminomethyl phenyl
121? ? Br? H? CH 2 3-chloro-5-bromo-4-p-methoxy-phenyl phenyl
122? ? Br? H? CH 2 2,3-two chloro-5-bromo-4-p-methoxy-phenyls
123? ? Br? H? CH 2 2,5-two bromo-3-chloro-4-p-methoxy-phenyls
124? ? Br? H? CH 2 2-iodo-3-chloro-5-bromo-4-p-methoxy-phenyl
125? ? Br? H? CH 2 2-fluoro-3-chloro-5-bromo-4-p-methoxy-phenyl
126? ? Br? H? CH 2 3-bromo-5-chloro-4-aminomethyl phenyl
127? ? Br? H? CH 2 2,5-two chloro-3-bromo-4-aminomethyl phenyls
128? ? Br? H? CH 2 2,3-two bromo-5-chloro-4-aminomethyl phenyls
129? ? Br? H? CH 2 2-iodo-3-bromo-5-chloro-4-aminomethyl phenyl
130? ? Br? H? CH 2 2-fluoro-3-bromo-5-chloro-4-aminomethyl phenyl
131? ? Br? H? CH 2 3-bromo-5-chloro-4-p-methoxy-phenyl
132? ? Br? H? CH 2 2,5-two chloro-3-bromo-4-p-methoxy-phenyls
133? ? Br? H? CH 2 2,3-two bromo-5-chloro-4-p-methoxy-phenyls
134? ? Br? H? CH 2 2-iodo-3-bromo-5-chloro-4-p-methoxy-phenyl
135? ? Br? H? CH 2 2-fluoro-3-bromo-5-chloro-4-p-methoxy-phenyl
136? ? Br? H? CH 2 3,5-dimethoxy-4 '-trifluoromethyl
137? ? Br? H? CH 2 2-chloro-3,5-dimethoxy-4 '-trifluoromethyl
138? ? Br? H? CH 2 2-bromo-3,5-dimethoxy-4 '-trifluoromethyl
139? ? Br? H? CH 2 2-iodo-3,5-dimethoxy-4 '-trifluoromethyl
140? ? Br? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-trifluoromethyl
141? ? Br? H? CH 2 3,5-two bromo-4-Trifluoromethoxyphen-ls
142? ? Br? H? CH 2 2-chloro-3,5-two bromo-4-Trifluoromethoxyphen-ls
143? ? Br? H? CH 2 2,3,5-three bromo-4-Trifluoromethoxyphen-ls
144? ? Br? H? CH 2 2-iodo-3,5-two bromo-4-Trifluoromethoxyphen-ls
145? ? Br? H? CH 2 2-fluoro-3,5-two bromo-4-Trifluoromethoxyphen-ls
146? ? Br? H? CH 2 3,5-dimethyl-4-p-methoxy-phenyl
147? ? Br? H? CH 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
148? ? Br? H? CH 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
149? ? Br? H? CH 2 2-iodo-3,5-dimethyl-4-p-methoxy-phenyl
150? ? Br? H? CH 2 2-fluoro-3,5-dimethyl-4-p-methoxy-phenyl
151? ? Br? H? CH 2 3,5-dimethyl-4-bromophenyl
152? ? Br? H? CH 2 2-chloro-3,5-dimethyl-4-bromophenyl
153? ? Br? H? CH 2 2,4-two bromo-3,5-3,5-dimethylphenyl
154? ? Br? H? CH 2 2-iodo-3,5-dimethyl-4-bromophenyl
155? ? Br? H? CH 2 2-fluoro-3,5-dimethyl-4-bromophenyl
156? ? Br? H? CH 2 3,5-dimethyl-4-chloro-phenyl-
157? ? Br? H? CH 2 2,4-two chloro-3,5-3,5-dimethylphenyl
158? ? Br? H? CH 2 2-bromo-3,5-dimethyl-4-chloro-phenyl-
159? ? Br? H? CH 2 2-iodo-3,5-dimethyl-4-chloro-phenyl-
160? ? F? H? CH 2 3,4, the 5-trimethoxyphenyl
161? ? F? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
162? ? F? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
163? ? F? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
164? ? F? H? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
165? ? F? H? CH 2 3,4, the 5-trimethylphenyl
166? ? F? H? CH 2 2-chloro-3,4, the 5-trimethylphenyl
167? ? F? H? CH 2 2-bromo-3,4, the 5-trimethylphenyl
168? ? F? H? CH 2 2-iodo-3,4, the 5-trimethylphenyl
169? ? F? H? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
170? ? F? H? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
171? ? F? H? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
172? ? F? H? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
173? ? F? H? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
174? ? F? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
175? ? F? H? CH 2 3,5-two chloro-4-aminomethyl phenyls
176? ? F? H? CH 2 2,3,5-three chloro-4-aminomethyl phenyls
177? ? F? H? CH 2 2-bromo-3,5-two chloro-4-aminomethyl phenyls
178? ? F? H? CH 2 2-iodo-3,5-two chloro-4-aminomethyl phenyls
179? ? F? H? CH 2 2-fluoro-3,5-two chloro-4-aminomethyl phenyls
180? ? F? H? CH 2 3,5-two bromo-4-aminomethyl phenyls
181? ? F? H? CH 2 2-chloro-3,5-two bromo-4-aminomethyl phenyls
182? ? F? H? CH 2 2,3,5-three bromo-4-methyl phenyl phenyls
183? ? F? H? CH 2 2-iodo-3,5-two bromo-4-aminomethyl phenyls
184? ? F? H? CH 2 2-fluoro-3,5-two bromo-4-aminomethyl phenyls
185? ? F? H? CH 2 3,5-two chloro-4-p-methoxy-phenyls
186? ? F? H? CH 2 2,3,5-three chloro-4-p-methoxy-phenyls
187? ? F? H? CH 2 2-bromo-3,5-two chloro-4-p-methoxy-phenyls
188? ? F? H? CH 2 2-iodo-3,5-two chloro-4-p-methoxy-phenyls
189? ? F? H? CH 2 2-fluoro-3,5-two chloro-4-p-methoxy-phenyls
190? ? F? H? CH 2 3,5-two bromo-4-p-methoxy-phenyls
191? ? F? H? CH 2 2-chloro-3,5-two bromo-4-p-methoxy-phenyls
192? ? F? H? CH 2 2,3,5-three bromo-4-p-methoxy-phenyls
193? ? F? H? CH 2 2-iodo-3,5-two bromo-4-p-methoxy-phenyls
194? ? F? H? CH 2 2-fluoro-3,5-two bromo-4-p-methoxy-phenyls
195? ? F? H? CH 2 3-chloro-5-bromo-4-aminomethyl phenyl
196? ? F? H? CH 2 2,3-two chloro-5-bromo-4-aminomethyl phenyls
197? ? F? H? CH 2 2,5-two bromo-3-chloro-4-aminomethyl phenyls
198? ? F? H? CH 2 2-iodo-3-chloro-5-bromo-4-aminomethyl phenyl
199? ? F? H? CH 2 2-fluoro-3-chloro-5-bromo-4-aminomethyl phenyl
200? ? F? H? CH 2 3-chloro-5-bromo-4-p-methoxy-phenyl phenyl
201? ? F? H? CH 2 2,3-two chloro-5-bromo-4-p-methoxy-phenyls
202? ? F? H? CH 2 2,5-two bromo-3-chloro-4-p-methoxy-phenyls
203? ? F? H? CH 2 2-iodo-3-chloro-5-bromo-4-p-methoxy-phenyl
204? ? F? H? CH 2 2-fluoro-3-chloro-5-bromo-4-p-methoxy-phenyl
205? ? F? H? CH 2 3-bromo-5-chloro-4-aminomethyl phenyl
206? ? F? H? CH 2 22,5-two chloro-3-bromo-4-aminomethyl phenyls
207? ? F? H? CH 2 2,3-two bromo-5-chloro-4-aminomethyl phenyls
208? ? F? H? CH 2 2-iodo-3-bromo-5-chloro-4-aminomethyl phenyl
209? ? F? H? CH 2 2-fluoro-3-bromo-5-chloro-4-aminomethyl phenyl
210? ? F? H? CH 2 3-bromo-5-chloro-4-p-methoxy-phenyl
211? ? F? H? CH 2 2,5-two chloro-3-bromo-4-p-methoxy-phenyls
212? ? F? H? CH 2 2,3-two bromo-5-chloro-4-p-methoxy-phenyls
213? ? F? H? CH 2 2-iodo-3-bromo-5-chloro-4-p-methoxy-phenyl
214? ? F? H? CH 2 2-fluoro-3-bromo-5-chloro-4-p-methoxy-phenyl
215? ? F? H? CH 2 3,5-dimethoxy-4 '-trifluoromethyl
216? ? F? H? CH 2 2-chloro-3,5-dimethoxy-4 '-trifluoromethyl
217? ? F? H? CH 2 2-bromo-3,5-dimethoxy-4 '-trifluoromethyl
218? ? F? H? CH 2 2-iodo-3,5-dimethoxy-4 '-trifluoromethyl
? ? ? ? ? Phenyl
219? ? F? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-trifluoromethyl
220? ? F? H? CH 2 3,5-two bromo-4-Trifluoromethoxyphen-ls
221? ? F? H? CH 2 2-chloro-3,5-two bromo-4-Trifluoromethoxyphen-ls
222? ? F? H? CH 2 2,3,5-three bromo-4-Trifluoromethoxyphen-ls
223? ? F? H? CH 2 2-iodo-3,5-two bromo-4-Trifluoromethoxyphen-ls
224? ? F? H? CH 2 2-fluoro-3,5-two bromo-4-Trifluoromethoxyphen-ls
225? ? F? H? CH 2 3,5-dimethyl-4-p-methoxy-phenyl
226? ? F? H? CH 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
227? ? F? H? CH 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
228? ? F? H? CH 2 2-iodo-3,5-dimethyl-4-p-methoxy-phenyl
229? ? F? H? CH 2 2-fluoro-3,5-dimethyl-4-p-methoxy-phenyl
230? ? F? H? CH 2 3,5-dimethyl-4-bromophenyl
231? ? F? H? CH 2 2-chloro-3,5-dimethyl-4-bromophenyl
232? ? F? H? CH 2 2,4-two bromo-3,5-3,5-dimethylphenyl
233? ? F? H? CH 2 2-iodo-3,5-dimethyl-4-bromophenyl
234? ? F? H? CH 2 2-fluoro-3,5-dimethyl-4-bromophenyl
235? ? F? H? CH 2 3,5-dimethyl-4-chloro-phenyl-
236? ? F? H? CH 2 2,4-two chloro-3,5-3,5-dimethylphenyl
237? ? F? H? CH 2 2-bromo-3,5-dimethyl-4-chloro-phenyl-
238? ? F? H? CH 2 2-iodo-3,5-dimethyl-4-chloro-phenyl-
239? ? F? H? CH 2 2-fluoro-3,5-dimethyl-4-chloro-phenyl-
240? 25? Cl? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
241? 31? Cl? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
242? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
243? 33? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
244? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
245? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
246? 1? Cl? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
247? 4? Cl? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
248? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-bromopyridine-2-base
249? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-bromopyridine-2-base
250? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
251? ? Cl? H? CH 2 4,6-two bromo-3,5-dimethyl-pyridine 1-oxide-2-base
252? 18? Cl? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
253? 19? Cl? H? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
254? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-chloropyridine-2-base
255? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-chloropyridine-2-base
256? ? Cl? H? CH 2 4,6-two chloro-3,5-dimethyl-pyridine 1-oxide-2-base
257? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
258? 111? Cl? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
259? ? Cl? H? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
260? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-iodine pyridine-2-base
261? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-iodine pyridine-2-base
262? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-iodo-pyridine 1-oxide
? ? ? ? ? -2-base
263? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
264? 115? Cl? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
265? ? Cl? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
266? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine-2-base
267? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine-2-base
268? ? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
269? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
270? 117? Cl? H? CH 2 3,4,5-trimethylammonium-pyridine-2-base
271? ? Cl? H? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
272? ? Cl? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine-2-base
273? ? Cl? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine-2-base
274? ? Cl? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
275? ? Cl? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
276? ? Cl? H? CH 2 4,5,6-trimethoxy pyridine-2-base
277? ? Cl? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
278? ? Cl? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
279? ? Cl? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
280? ? Cl? H? CH 2 3-chloro-4,5,6-trimethoxy-pyridine 1-oxide-2-base
281? ? Cl? H? CH 2 3-bromo-4,5,6-trimethoxy-pyridine 1-oxide
? ? ? ? ? -2-base
282? ? Cl? H? CH 2 3,4,5-trimethoxy-pyridine-2-base
283? ? Cl? H? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
284? ? Cl? H? CH 2 3-bromo-3,4,5-trimethoxy-pyridine-2-base
285? ? Cl? H? CH 2 3-chloro-3,4,5-trimethoxy-pyridine-2-base
286? ? Cl? H? CH 2 3-chloro-3,4,5-trimethoxy-pyridine 1-oxide-2-base
287? ? Cl? H? CH 2 3-bromo-3,4,5-trimethoxy-pyridine 1-oxide-2-base
288? ? Cl? H? CH 2 4,5,6-trimethylpyridine-2-base
289? ? Cl? H? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
290? ? Cl? H? CH 2 3-bromo-4,5,6-trimethylpyridine-2-base
291? ? Cl? H? CH 2 3-chloro-4,5,6-trimethylpyridine-2-base
292? ? Cl? H? CH 2 3-chloro-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
293? ? Cl? H? CH 2 3-bromo-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
294? ? Cl? H? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
295? ? Cl? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
296? ? Cl? H? CH 2 3-bromo-4,6-dimethyl-5-methoxypyridine-2-base
297? ? Cl? H? CH 2 3-chloro-4,6-dimethyl-5-methoxypyridine-2-base
298? ? Cl? H? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
299? ? Cl? H? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
300? ? Cl? H? CH 2 4-bromo-5,6-dimethoxy-pyridine-2-base
301? ? Cl? H? CH 2 4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
302? ? Cl? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine-2-base
303? ? Cl? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine-2-base
304? ? Cl? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
305? ? Cl? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
306? ? Cl? H? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
307? ? Cl? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
308? ? Cl? H? CH 2 4,6-dimethyl-5-bromopyridine-3-base
309? ? Cl? H? CH 2 4,6-dimethyl-5-chloropyridine-3-base
310? ? Cl? H? CH 2 5,6-dimethyl-4-bromopyridine-3-base
311? ? Cl? H? CH2? 5,6-dimethyl-4-chloropyridine-3-base
312? ? Cl? H? CH 2 4,6-dimethyl-5-bromo-pyridine 1-oxide-pyridin-3-yl
313? ? Cl? H? CH 2 4,6-dimethyl-5-chloro-pyridine 1-oxide-pyridin-3-yl
314? ? Cl? H? CH 2 5,6-dimethyl-4-bromo-pyridine 1-oxide-pyridin-3-yl
315? ? Cl? H? CH 2 5,6-dimethyl-4-chloro-pyridine 1-oxide-pyridin-3-yl
316? ? Cl? H? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
317? ? Cl? H? CH 2 2,6-dimethyl-pyridin-4-yl
318? ? Cl? H? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
319? ? Cl? H? CH 2 2,3,6-trimethoxy-pyridin-4-yl
320? ? Cl? H? CH 2 2,6-dimethyl-3-bromopyridine-4 base
321? ? Cl? H? CH 2 2,6-dimethyl-3-chloropyridine-4 base
322? ? Cl? H? CH 2 2,6-two chloro-3-bromopyridine-4-bases
323? ? Cl? H? CH 2 2,6-two bromo-3-chloropyridine-4-bases
324? ? Cl? H? CH 2 2,3,6-three chloro-pyridin-4-yls
325? ? Cl? H? CH 2 2,3,6-three bromo-pyridin-4-yls
326? ? Cl? H? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
327? ? Cl? H? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
328? ? Cl? H? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
329? ? Cl? H? CH 2 2,3,6-trimethoxy-1-oxygen-pyridin-4-yl
330? ? Cl? H? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
331? ? Cl? H? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
332? ? Cl? H? CH 2 2,6-two chloro-3-bromo-1-oxygen-pyridin-4-yls
333? ? Cl? H? CH 2 2,6-two bromo-3-chloro-1-oxygen-pyridin-4-yls
334? ? Cl? H? CH 2 2,3,6-three chloro-1-oxygen-pyridin-4-yls
335? ? Cl? H? CH 2 2,3,6-three bromo-1-oxygen-pyridin-4-yls
336? ? Cl? H? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
337? ? Cl? H? CH 2 5,6-dimethyl-4-iodine pyridine-3-base
338? ? Cl? H? CH 2 4,5,6-trichloropyridine-3-base
339? ? Cl? H? CH 2 4,5,6-pyridinium tribromide-3-base
340? 21? Br? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
341? 24? Br? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
342? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
343? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine
? ? ? ? ? -2-base
344? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
345? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
346? 5? Br? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
347? 6? Br? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
348? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-bromopyridine-2-base
349? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-bromopyridine-2-base
350? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
351? ? Br? H? CH 2 4,6-two bromo-3,5-dimethyl-pyridine 1-oxide-2-base
352? ? Br? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
353? ? Br? H? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
354? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-chloropyridine-2-base
355? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-chloropyridine-2-base
356? ? Br? H? CH 2 4,6-two chloro-3,5-dimethyl-pyridine 1-oxide-2-base
357? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
358? ? Br? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
359? ? Br? H? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
360? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-iodine pyridine-2-base
361? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-iodine pyridine-2-base
362? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
363? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
364? ? Br? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
365? ? Br? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
366? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine-2-base
367? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine-2-base
368? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
369? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
370? 118? Br? H? CH 2 3,4,5-trimethylammonium-pyridine-2-base
371? 119? Br? H? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
372? ? Br? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine-2-base
373? ? Br? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine-2-base
374? ? Br? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
375? ? Br? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
376? ? Br? H? CH 2 3,4,5-trimethoxy-pyridine-2-base
377? ? Br? H? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
378? ? Br? H? CH 2 6-bromo-3,4,5-trimethoxy-pyridine-2-base
379? ? Br? H? CH 2 6-chloro-3,4,5-trimethoxy-pyridine-2-base
380? ? Br? H? CH 2 6-chloro-3,4,5-trimethoxy-pyridine 1-oxide-2-base
381? ? Br? H? CH 2 6-bromo-3,4,5-trimethoxy-pyridine 1-oxide-2-base
382? ? Br? H? CH 2 4,5,6-trimethoxy pyridine-2-base
383? ? Br? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
384? ? Br? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
385? ? Br? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
386? ? Br? H? CH 2 3-chloro-4,5,6-trimethoxy-pyridine 1-oxide-2-base
387? ? Br? H? CH 2 3-bromo-4,5,6-trimethoxy-pyridine 1-oxide-2-base
388? ? Br? H? CH 2 4,5,6-trimethoxy pyridine-2-base
389? ? Br? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
390? ? Br? H? CH 2 3-bromo-4,5,6-trimethylpyridine-2-base
391? ? Br? H? CH 2 3-chloro-4,5,6-trimethylpyridine-2-base
392? ? Br? H? CH 2 3-chloro-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
393? ? Br? H? CH 2 3-bromo-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
394? ? Br? H? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
395? ? Br? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
396? ? Br? H? CH 2 3-bromo-4,6-dimethyl-5-methoxypyridine-2-base
397? ? Br? H? CH 2 3-chloro-4,6-dimethyl-5-methoxypyridine-2-base
398? ? Br? H? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
399? ? Br? H? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
400? ? Br? H? CH 2 4-bromo-5,6-dimethoxy-pyridine-2-base
401? ? Br? H? CH 2 4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
402? ? Br? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine-2-
? ? ? ? ? Base
403? ? Br? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine-2-base
404? ? Br? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
405? ? Br? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
406? ? Br? H? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
407? ? Br? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
408? ? Br? H? CH 2 4,6-dimethyl-5-bromopyridine-3-base
409? ? Br? H? CH 2 4,6-dimethyl-5-chloropyridine-3-base
410? ? Br? H? CH 2 5,6-dimethyl-4-bromopyridine-3-base
411? ? Br? H? CH 2 5,6-dimethyl-4-chloropyridine-3-base
412? ? Br? H? CH 2 4,6-dimethyl-5-bromo-pyridine 1-oxide-pyridin-3-yl
413? ? Br? H? CH 2 4,6-dimethyl-5-chloro-pyridine 1-oxide-pyridin-3-yl
414? ? Br? H? CH 2 5,6-dimethyl-4-bromo-pyridine 1-oxide-pyridin-3-yl
415? ? Br? H? CH 2 5,6-dimethyl-4-chloro-pyridine 1-oxide-pyridin-3-yl
416? ? Br? H? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
417? ? Br? H? CH 2 2,6-dimethyl-pyridin-4-yl
418? ? Br? H? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
419? ? Br? H? CH 2 2,3,6-trimethoxy-pyridin-4-yl
420? ? Br? H? CH 2 2,6-dimethyl-3-bromopyridine-4 base
421? ? Br? H? CH 2 2,6-dimethyl-3-chloropyridine-4 base
422? ? Br? H? CH 2 2,6-two chloro-3-bromopyridine-4-bases
423? ? Br? H? CH 2 2,6-two bromo-3-chloropyridine-4-bases
424? ? Br? H? CH 2 2,3,6-three chloro-pyridin-4-yls
425? ? Br? H? CH 2 2,3,6-three bromo-pyridin-4-yls
426? ? Br? H? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
427? ? Br? H? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
428? ? Br? H? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
429? ? Br? H? CH 2 2,3,6-trimethoxy-1-oxygen-pyridin-4-yl
430? ? Br? H? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
431? ? Br? H? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
432? ? Br? H? CH 2 2,6-two chloro-3-bromo-1-oxygen-pyridin-4-yls
433? ? Br? H? CH 2 2,6-two bromo-3-chloro-1-oxygen-pyridin-4-yls
434? ? Br? H? CH 2 2,3,6-three chloro-1-oxygen-pyridin-4-yls
435? ? Br? H? CH 2 2,3,6-three bromo-1-oxygen-pyridin-4-yls
436? ? Br? H? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
437? ? Br? H? CH 2 5,6-dimethyl-4-iodine pyridine-3-base
438? ? Br? H? CH 2 4,5,6-trichloropyridine-3-base
439? ? Br? H? CH 2 4,5,6-pyridinium tribromide-3-base
440? ? F? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
441? ? F? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
442? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
443? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
444? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
445? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
446? ? F? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
447? ? F? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
448? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-bromopyridine-2-base
449? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-bromopyridine-2-base
450? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
451? ? F? H? CH 2 4,6-two bromo-3,5-dimethyl-pyridine 1-oxide-2-base
452? ? F? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
453? ? F? H? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
454? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-chloropyridine-2-base
455? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-chloropyridine-2-base
456? ? F? H? CH 2 4,6-two chloro-3,5-dimethyl-pyridine 1-oxide-2-base
457? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
458? ? F? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
459? ? F? H? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
460? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-iodine pyridine-2-base
461? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-iodine pyridine-2-base
462? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
463? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
464? ? F? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
465? ? F? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
466? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine-2-base
467? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine-2-base
468? ? F? H? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
469? ? F? H? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
470? ? F? H? CH 2 3,4,5-trimethylammonium-pyridine-2-base
471? ? F? H? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
472? ? F? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine-2-base
473? ? F? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine-2-base
474? ? F? H? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
475? ? F? H? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
476? ? F? H? CH 2 3,4,5-trimethoxy-pyridine-2-base
477? ? F? H? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
478? ? F? H? CH 2 6-bromo-3,4,5-trimethoxy-pyridine-2-base
479? ? F? H? CH 2 6-chloro-3,4,5-trimethoxy-pyridine-2-base
480? ? F? H? CH 2 6-chloro-3,4,5-trimethoxy-pyridine 1-oxide-2-base
481? ? F? H? CH 2 6-bromo-3,4,5-trimethoxy-pyridine 1-oxide-2-base
482? ? F? H? CH 2 4,5,6-trimethoxy pyridine-2-base
483? ? F? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
484? ? F? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
485? ? F? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
486? ? F? H? CH 2 3-chloro-4,5,6-trimethoxy-pyridine 1-oxide
? ? ? ? ? -2-base
487? ? F? H? CH 2 3-bromo-4,5,6-trimethoxy-pyridine 1-oxide-2-base
488? ? F? H? CH 2 4,5,6-trimethylammonium-pyridine-2-base
489? ? F? H? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
490? ? F? H? CH 2 3-bromo-4,5,6-trimethylpyridine-2-base
491? ? F? H? CH 2 3-chloro-4,5,6-trimethylpyridine-2-base
492? ? F? H? CH 2 3-chloro-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
493? ? F? H? CH 2 3-bromo-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
494? ? F? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
495? ? F? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
496? ? F? H? CH 2 3-bromo-4,6-dimethyl-5-methoxypyridine-2-base
497? ? F? H? CH 2 3-chloro-4,6-dimethyl-5-methoxypyridine-2-base
498? ? F? H? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
499? ? F? H? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
500? ? F? H? CH 2 4-bromo-5,6-dimethoxy-pyridine-2-base
501? ? F? H? CH 2 4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
502? ? F? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine-2-base
503? ? F? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine-2-base
504? ? F? H? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
505? ? F? H? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
506? ? F? H? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
507? ? F? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
508? ? F? H? CH 2 4,6-dimethyl-5-bromopyridine-3-base
509? ? F? H? CH 2 4,6-dimethyl-5-chloropyridine-3-base
510? ? F? H? CH 2 5,6-dimethyl-4-bromopyridine-3-base
511? ? F? H? CH 2 5,6-dimethyl-4-chloropyridine-3-base
512? ? F? H? CH 2 4,6-dimethyl-5-bromo-pyridine 1-oxide-pyridin-3-yl
513? ? F? H? CH 2 4,6-dimethyl-5-chloro-pyridine 1-oxide-pyridin-3-yl
514? ? F? H? CH 2 5,6-dimethyl-4-bromo-pyridine 1-oxide-pyridin-3-yl
515? ? F? H? CH 2 5,6-dimethyl-4-chloro-pyridine 1-oxide-pyridin-3-yl
516? ? F? H? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
517? ? F? H? CH 2 2,6-dimethyl-pyridin-4-yl
518? ? F? H? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
519? ? F? H? CH 2 2,3,6-trimethoxy-pyridin-4-yl
520? ? F? H? CH 2 2,6-dimethyl-3-bromopyridine-4 base
521? ? F? H? CH 2 2,6-dimethyl-3-chloropyridine-4 base
522? ? F? H? CH 2 2,6-two chloro-3-bromopyridine-4-bases
523? ? F? H? CH 2 2,6-two bromo-3-chloropyridine-4-bases
524? ? F? H? CH 2 2,3,6-three chloro-pyridin-4-yls
525? ? F? H? CH 2 2,3,6-three bromo-pyridin-4-yls
526? ? F? H? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
527? ? F? H? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
528? ? F? H? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
529? ? F? H? CH 2 2,3,6-trimethoxy-1-oxygen-pyridin-4-yl
530? ? F? H? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
531? ? F? H? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
532? ? F? H? CH 2 2,6-two chloro-3-bromo-1-oxygen-pyridin-4-yls
533? ? F? H? CH 2 2,6-two bromo-3-chloro-1-oxygen-pyridin-4-yls
534? ? F? H? CH 2 2,3,6-three chloro-1-oxygen-pyridin-4-yls
536? ? F? H? CH 2 2,3,6-three bromo-1-oxygen-pyridin-4-yls
537? ? F? H? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
538? ? F? H? CH 2 5,6-dimethyl-4-iodine pyridine-3-base
539? ? F? H? CH 2 4,5,6-trichloropyridine-3-base
540? ? Cl? Cl? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
541? ? Br? Cl? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
542? ? Cl? Br? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
543? ? Br? Br? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
544? ? Cl? N 3 CH 2 3,5-dimethyl-4-methoxypyridine-2-base
545? ? Br? N 3 CH 2 3,5-dimethyl-4-methoxypyridine-2-base
546? ? F? Cl? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
547? ? F? Br? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
548? ? Cl? CN? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
549? ? Br? CN? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
550? ? Cl? Cl? CH 2 3,5-dimethyl-4-bromopyridine-2-base
551? ? Br? Cl? CH 2 3,5-dimethyl-4-bromopyridine-2-base
552? ? Cl? Br? CH 2 3,5-dimethyl-4-bromopyridine-2-base
553? ? Br? Br? CH 2 3,5-dimethyl-4-bromopyridine-2-base
554? ? Cl? N 3 CH 2 3,5-dimethyl-4-bromopyridine-2-base
555? ? Br? N 3 CH 2 3,5-dimethyl-4-bromopyridine-2-base
556? ? F? Cl? CH 2 3,5-dimethyl-4-bromopyridine-2-base
557? ? F? Br? CH 2 3,5-dimethyl-4-bromopyridine-2-base
558? ? Cl? CN? CH 2 3,5-dimethyl-4-bromopyridine-2-base
559? ? Br? CN? CH 2 3,5-dimethyl-4-bromopyridine-2-base
560? ? Cl? Cl? CH 2 3,5-dimethyl-4-chloropyridine-2-base
561? ? Br? Cl? CH 2 3,5-dimethyl-4-chloropyridine-2-base
562? ? Cl? Br? CH 2 3,5-dimethyl-4-chloropyridine-2-base
563? ? Br? Br? CH 2 3,5-dimethyl-4-chloropyridine-2-base
564? ? Cl? N 3 CH 2 3,5-dimethyl-4-chloropyridine-2-base
565? ? Br? N 3 CH 2 3,5-dimethyl-4-chloropyridine-2-base
566? ? F? Cl? CH 2 3,5-dimethyl-4-chloropyridine-2-base
567? ? F? Br? CH 2 3,5-dimethyl-4-chloropyridine-2-base
568? ? Cl? CN? CH 2 3,5-dimethyl-4-chloropyridine-2-base
569? ? Br? CN? CH 2 3,5-dimethyl-4-chloropyridine-2-base
570? ? Cl? Cl? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
571? ? Br? Cl? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
572? ? Cl? Br? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
573? ? Br? Br? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
574? ? Cl? N 3 CH 2 3,5-dimethyl-4-iodine pyridine-2-base
575? ? Br? N 3 CH 2 3,5-dimethyl-4-iodine pyridine-2-base
576? ? F? Cl? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
577? ? F? Br? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
578? ? Cl? CN? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
579? ? Br? CN? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
580? ? Cl? Cl? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
581? ? Br? Cl? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
582? ? Cl? Br? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
583? ? Br? Br? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
584? ? Cl? Cl? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
585? ? Br? Cl? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
586? ? Cl? Br? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
587? ? Br? Br? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
588? 7? Cl? H? CH 2 3,5-dimethyl-4-pyridone-2-base
589? 8? Cl? H? CH 2 3,5-dimethyl-4-ethoxy pyridine-2-base
590? 9? Cl? H? CH 2 3,5-dimethyl-4-allyloxy pyridine-2-base
591? 10? Cl? H? CH 2 3,5-dimethyl-4-(2-oxyethyl group-oxyethyl group) pyridine-2-base
592? 11? Cl? H? CH 2 3,5-dimethyl-4-isopropoxy pyridine-2-base
593? 12? Cl? H? CH 2 3,5-dimethyl-4-cyclo propyl methoxy pyridine-2-base
594? 13? Cl? H? CH 2 3,5-dimethyl-4-(3-methyl-butoxy) pyridine-2-base
595? 14? Cl? H? CH 2 3,5-dimethyl-4-isobutoxy pyridine-2-base
596? 15? Cl? H? CH 2 3,5-dimethyl-4-(2-acetoxyl group-oxyethyl group) pyridine-2-base
597? 16? Cl? H? CH 2 3,5-dimethyl-4-(3-acetoxyl group-propoxy-) pyridine-2-base
598? 17? Cl? H? CH 2 3,5-dimethyl-4-propoxy-pyridine-2-base
599? 20? Cl? H? CH 2 3,5-lutidine-2-base
600? 32? Cl? H? CH 2 3,5-dimethyl-4-methoxyl group-1-methoxypyridine-2-base
601? 34? Cl? H? CH 2 5-methoxyl group-4-methoxymethyl-6-methyl
? ? ? ? ? Pyridin-3-yl
602? 35? Cl? H? CH 2 5-oxyethyl group-4-hydroxymethyl-6-picoline-3-base
604? 36? Cl? H? CH 2 3,5-dimethyl-4-aminopyridine-2-base
605? 37? Cl? H? CH 2 3-methoxyl group-5-methoxymethyl-4-picoline-2-base
606? 38? Cl? H? CH 2 5-chloro-6-methoxypyridine-3-base
607? 39? Cl? H? CH 2 3,4-dimethoxy-pyridine-2-base
608? 40? Cl? H? CH 2 3-methoxyl group-6-picoline-2-base
609? 42? H? H? CH 2 4-methoxyl group-3,5-lutidine-2-base
610? 45? Cl? Br? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
611? 47? Cl? Bu? CH 2 3,4, the 5-trimethoxyphenyl
612? 49? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-acetoxyl group phenyl
613? 50? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-hydroxy phenyl
614? 52? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-allyloxy phenyl
615? 53? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-chloromethyl oxygen base phenyl
616? 54? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-chloroethoxy phenyl
617? 55? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-cyclo propyl methoxy phenyl
618? 56? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-ethoxyl phenenyl
619? 57? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-propoxy-phenyl
620? 58? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-butoxy phenyl
621? 59? Cl? H? CH 2 3-methoxymethyl oxygen-6-picoline-2-base
622? 60? Cl? H? CH 2 3H-benzothiazole-2-thioketones
623? 61? Cl? H? CH 2 2, the 5-3,5-dimethylphenyl
624? 62? Cl? H? CH 2 Isoquinolyl-1
625? 63? Cl? H? CH 2 Benzo [1,2,5] thiadiazoles-5-base
626? 64? Cl? H? CH 2 1-methyl isophthalic acid H-benzotriazole-5-base
627? 65? Cl? H? CH 2 6-chloro-benzo [1,2,5] thiadiazoles-5-base
628? 66? Cl? H? CH 2 Benzo [1,2,5] thiadiazoles-4-base
629? 67? Cl? H? CH 2 6-fluoro-4a, 8a-dihydro-4H-benzo [1,3] dioxin-8-base
630? 68? Cl? H? CH 2 2-methoxyl group-4-acetylphenyl
631? 69? Cl? H? CH 2 The 3-Trifluoromethoxyphen-l
632? 70? Cl? H? CH 2 2-fluoro-3-trifluoromethyl
633? 71? Cl? H? CH 2 2-fluoro-4, the 5-Dimethoxyphenyl
634? 72? Cl? H? CH 2 2, the 3-Dimethoxyphenyl
635? 73? Cl? H? CH 2 3, the 4-Dimethoxyphenyl
636? 74? Me? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
637? 75? Cl? H? CH 2 2-chloro-4, the 5-Dimethoxyphenyl
638? 76? Cl? H? CH 2 2-iodo-4, the 5-Dimethoxyphenyl
639? 78? Cl? H? CH 2 6-chloro-benzo [1,3] dioxole-5-base
640? 79? Cl? H? CH 2 2,4-dimethoxy-3-aminomethyl phenyl
641? 80? Cl? H? CH 2 2-chloro-3, the 4-Dimethoxyphenyl
642? 81? Cl? H? CH 2 The 3-p-methoxy-phenyl
643? 82? Cl? H? CH 2 2,6-two bromo-3,5-Dimethoxyphenyl
644? 83? Cl? H? CH 2 2-bromo-3, the 5-Dimethoxyphenyl
645? 84? Cl? H? CH 2 3, the 5-Dimethoxyphenyl
646? 86? Cl? H? CH 2 2, the 5-Dimethoxyphenyl
647? 87? Cl? Br? CH 2 2, the 5-Dimethoxyphenyl
648? 88? Cl? H? CH 2 2-nitro-4, the 5-Dimethoxyphenyl
649? 89? Cl? Br? CH 2 2-nitro-4, the 5-Dimethoxyphenyl
650? 90? Cl? H? CH 2 2, the 5-dichlorophenyl
651? 91? Cl? H? CH 2 2,3, the 5-trifluorophenyl
652? 92? Cl? H? C(O)? 3,4, the 5-trimethoxyphenyl
653? 95? Cl? H? CH 2 3, the 5-dichlorophenyl
654? 96? Cl? H? CH 2 3, the 4-dichlorophenyl
655? 97? Cl? Br? CH 2 3, the 4-dichlorophenyl
656? 99? Cl? H? CH 2 2,6-two chloro-3,4,5-trimethoxyphenyl
657? 100? OH? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
658? 103? SEt? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
659? 104? OMe? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
660? 105? NH 2 H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
661? 107? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-methoxymethyl oxygen base phenyl
662? 108? Cl? H? CH 2 Benzothiazole-2-base
663? 109? Cl? H? CH 2 The 4-p-methoxy-phenyl
664? 110? Cl? H? CH 2 2-bromo-4, the basic phenyl of 5-dimethoxy
665? 112? Cl? H? CH 2 4-toluquinoline-2-base
666? 113? Br? H? CH 2 4-toluquinoline-2-base
667? 114? Br? H? CH 2 4-methyl isophthalic acid-oxygen-quinoline-2-base
668? 116? Cl? H? CH 2 6-chloro-benzothiazole-2-base
669? ? Cl? H? CH 2 4,5,6-trimethoxy-pyridin-3-yl
670? ? Cl? H? CH 2 4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
671? ? Cl? H? CH 2 2-bromo-4,5,6-trimethoxy-pyridin-3-yl
672? ? Cl? H? CH 2 2-chloro-4,5,6-trimethoxy-pyridin-3-yl
673? ? Cl? H? CH 2 2-chloro-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
674? ? Cl? H? CH 2 2-bromo-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
675? ? Cl? H? CH 2 4,5,6-trimethylpyridine-3-base
676? ? Cl? H? CH 2 4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl
677? ? Cl? H? CH 2 2-bromo-4,5,6-trimethylpyridine-3-base
678? ? Cl? H? CH 2 2-chloro-4,5,6-trimethylpyridine-3-base
679? ? Cl? H? CH 2 2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
680? ? Cl? H? CH 2 2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
681? ? Cl? H? CH 2 2-iodo-4,5,6-trimethylpyridine-3-base
682? ? Cl? H? CH 2 2-iodo-4,5,6-trimethylpyridine-3-base
683? ? Br? H? CH 2 4,5,6-trimethoxy-pyridin-3-yl
684? ? Br? H? CH 2 4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
685? ? Br? H? CH 2 2-bromo-4,5,6-trimethoxy-pyridin-3-yl
686? ? Br? H? CH 2 2-chloro-4,5,6-trimethoxy-pyridin-3-yl
687? ? Br? H? CH 2 2-chloro-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
688? ? Br? H? CH 2 2-bromo-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
689? ? Br? H? CH 2 4,5,6-trimethylpyridine-3-base
690? ? Br? H? CH 2 4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl
691? ? Br? H? CH 2 2-bromo-4,5,6-trimethylpyridine-3-base
692? ? Br? H? CH 2 2-chloro-4,5,6-trimethylpyridine-3-base
693? ? Br? H? CH 2 2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
694? ? Br? H? CH 2 2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
695? ? I? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
696? ? I? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
697? ? I? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
698? ? I? H? CH 2 4,5,6-trimethoxy-pyridine-2-base
699? ? I? H? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine-2-base
700? ? I? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
701? ? I? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
702? ? I? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
703? ? I? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
704? ? I? H? CH 2 3,4, the 5-trimethoxyphenyl
705? ? I? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
706? ? I? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
707? ? I? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
708? ? I? H? CH 2 3,4,5-trimethylpyridine-2-base
709? ? I? H? CH 2 4,5,6-trimethylpyridine-3-base
710? ? I? H? CH 2 3,5-dimethyl-4-thiomethyl pyridine-2-base
711? ? I? H? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
712? ? I? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
713? ? I? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
714? ? I? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
Compound useful in the table 2 is: 2,3,11,44,82,83,242,243,245,248,249,254,255,260,266,272,273,278,279,284,286,287,308,309,343,348,349,354,366,367,372,373,671 and 697 (what therefrom select is 2,242,243,248,254,260,266,272,278,284,286,287,308,343,348,349,354,372,373,671 and 697).
Table 3: formula III A, R 2=NH 2Example compound
No.? Embodiment R 1 R 3 R 4 R 5
1? 5? Cl? H? CH 2 3,4, the 5-trimethoxyphenyl
2? 6? Cl? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
3? ? Cl? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
4? ? Cl? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
5? ? Cl? H? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
6? ? Cl? H? CH 2 3,4, the 5-trimethylphenyl
7? ? Cl? H? CH 2 2-chloro-3,4, the 5-trimethylphenyl
8? ? Cl? H? CH 2 2-bromo-3,4, the 5-trimethylphenyl
9? ? Cl? H? CH 2 2-iodo-3,4, the 5-trimethylphenyl
10? ? Cl? H? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
11? ? Cl? H? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
12? ? Cl? H? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
13? ? Cl? H? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
14? ? Cl? H? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
15? ? Cl? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
16? ? Cl? i-pr? CH 2 3,4, the 5-trimethoxyphenyl
17? ? Cl? i-pr? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
18? ? Cl? i-pr? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
19? ? Cl? i-pr? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
20? ? Cl? i-pr? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
21? ? Cl? i-pr? CH 2 3,4, the 5-trimethylphenyl
22? ? Cl? i-pr? CH 2 2-chloro-3,4, the 5-trimethylphenyl
23? ? Cl? i-pr? CH 2 2-bromo-3,4, the 5-trimethylphenyl
24? ? Cl? i-pr? CH 2 2-iodo-3,4, the 5-trimethylphenyl
25? ? Cl? i-pr? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
26? ? Cl? i-pr? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
27? ? Cl? i-pr? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
28? ? Cl? i-pr? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
29? ? Cl? i-pr? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
30? ? Cl? i-pr? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
31? ? Cl? Et? CH 2 3,4, the 5-trimethoxyphenyl
32? ? Cl? Et? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
33? ? Cl? Et? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
34? ? Cl? Et? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
35? ? Cl? Et? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
36? ? Cl? Et? CH 2 3,4, the 5-trimethylphenyl
37? ? Cl? Et? CH 2 2-chloro-3,4, the 5-trimethylphenyl
38? ? Cl? Et? CH 2 2-bromo-3,4, the 5-trimethylphenyl
39? ? Cl? Et? CH 2 2-iodo-3,4, the 5-trimethylphenyl
40? ? Cl? Et? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
41? ? Cl? Et? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
42? ? Cl? Et? CH 2 2-chloro-3,5-dimethoxy-4 '-methylbenzene
? ? ? ? ? Base
43? ? Cl? Et? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
44? ? Cl? Et? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
45? ? Cl? Et? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
46? 27? Cl? Me? CH 2 3,4, the 5-trimethoxyphenyl
47? ? Cl? Me? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
48? ? Cl? Me? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
49? ? Cl? Me? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
50? ? Cl? Me? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
51? ? Cl? Me? CH 2 3,4, the 5-trimethylphenyl
52? ? Cl? Me? CH 2 2-chloro-3,4, the 5-trimethylphenyl
53? ? Cl? Me? CH 2 2-bromo-3,4, the 5-trimethylphenyl
54? ? Cl? Me? CH 2 2-iodo-3,4, the 5-trimethylphenyl
55? ? Cl? Me? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
56? ? Cl? Me? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
57? ? Cl? Me? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
58? ? Cl? Me? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
59? ? Cl? Me? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
60? ? Cl? Me? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
61? ? Cl? Ph? CH 2 3,4, the 5-trimethoxyphenyl
62? ? Cl? Ph? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
63? ? Cl? Ph? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
64? ? Cl? Ph? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
65? ? Cl? Ph? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
66? ? Cl? Ph? CH 2 3,4, the 5-trimethylphenyl
67? ? Cl? Ph? CH 2 2-chloro-3,4, the 5-trimethylphenyl
68? ? Cl? Ph? CH 2 2-bromo-3,4, the 5-trimethylphenyl
69? ? Cl? Ph? CH 2 2-iodo-3,4, the 5-trimethylphenyl
70? ? Cl? Ph? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
71? ? Cl? Ph? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
72? ? Cl? Ph? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
73? ? Cl? Ph? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
74? ? Cl? Ph? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
75? ? Cl? Ph? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
76? ? Cl? 2-Py? CH 2 3,4, the 5-trimethoxyphenyl
77? ? Cl? 2-Py? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
78? ? Cl? 2-Py? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
79? ? Cl? 2-Py? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
80? ? Cl? 2-Py? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
81? ? Cl? 2-Py? CH 2 3,4, the 5-trimethylphenyl
82? ? Cl? 2-Py? CH 2 2-chloro-3,4, the 5-trimethylphenyl
83? ? Cl? 2-Py? CH 2 2-bromo-3,4, the 5-trimethylphenyl
84? ? Cl? 2-Py? CH 2 2-iodo-3,4, the 5-trimethylphenyl
85? ? Cl? 2-Py? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
86? ? Cl? 2-Py? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
87? ? Cl? 2-Py? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
88? ? Cl? 2-Py? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
89? ? Cl? 2-Py? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
90? ? Cl? 2-Py? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
91? ? Cl? Me? CH 2 3,4, the 5-trimethoxyphenyl
92? ? Cl? Me? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
93? ? Cl? Me? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
94? ? Cl? Me? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
95? ? Cl? Me? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
96? ? Cl? Ph? CH 2 3,4, the 5-trimethylphenyl
97? ? Cl? Ph? CH 2 2-chloro-3,4, the 5-trimethylphenyl
98? ? Cl? Ph? CH 2 2-bromo-3,4, the 5-trimethylphenyl
99? ? Cl? Ph? CH 2 2-iodo-3,4, the 5-trimethylphenyl
100? ? Cl? Ph? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
101? ? Cl? Ph? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
102? ? Cl? Ph? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
103? ? Cl? Ph? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
104? ? Cl? Ph? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
105? ? Cl? Pr? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
106? ? Cl? Pr? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
107? ? Cl? Pr? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
108? ? Cl? Pr? CH 2 2-bromo-3,5-dimethoxy-4 '-methylbenzene
? ? ? ? ? Base
109? ? Cl? Pr? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
110? ? Cl? Pr? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
111? ? Cl? Pr? CH 2 3,4, the 5-trimethoxyphenyl
112? ? Cl? Pr? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
113? ? Cl? Pr? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
114? ? Cl? Pr? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
115? ? Cl? Pr? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
116? ? Cl? Pr? CH 2 3,4, the 5-trimethylphenyl
117? ? Cl? Pr? CH 2 2-chloro-3,4, the 5-trimethylphenyl
118? ? Cl? Pr? CH 2 2-bromo-3,4, the 5-trimethylphenyl
119? ? Cl? Pr? CH 2 2-iodo-3,4, the 5-trimethylphenyl
120? ? Cl? Pr? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
121? ? Cl? Pr? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
122? ? Cl? Pr? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
123? ? Cl? Pr? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
124? ? Cl? Pr? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
125? ? Cl? Pr? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
126? ? Br? H? CH 2 3,4, the 5-trimethoxyphenyl
127? ? Br? H? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
128? ? Br? H? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
129? ? Br? H? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
130? ? Br? H? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
131? ? Br? H? CH 2 3,4, the 5-trimethylphenyl
132? ? Br? H? CH 2 2-chloro-3,4, the 5-trimethylphenyl
133? ? Br? H? CH 2 2-bromo-3,4, the 5-trimethylphenyl
134? ? Br? H? CH 2 2-iodo-3,4, the 5-trimethylphenyl
135? ? Br? H? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
136? ? Br? H? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
137? ? Br? H? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
138? ? Br? H? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
139? ? Br? H? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
140? ? Br? H? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
141? ? Cl? i-Bu? CH 2 3,4, the 5-trimethoxyphenyl
142? ? Cl? i-Bu? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
143? ? Cl? i-Bu? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
144? ? Cl? i-Bu? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
145? ? Cl? i-Bu? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
146? ? Cl? i-Bu? CH 2 3,4, the 5-trimethylphenyl
147? ? Cl? i-Bu? CH 2 2-chloro-3,4, the 5-trimethylphenyl
148? ? Cl? i-Bu? CH 2 2-bromo-3,4, the 5-trimethylphenyl
149? ? Cl? i-Bu? CH 2 2-iodo-3,4, the 5-trimethylphenyl
150? ? Cl? i-Bu? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
151? ? Cl? i-Bu? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
152? ? Cl? i-Bu? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
153? ? Cl? i-Bu? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
154? ? Cl? i-Bu? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
155? ? Cl? i-Bu? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
156? ? Cl? CN? CH 2 3,4, the 5-trimethoxyphenyl
157? ? Cl? CN? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
158? ? Cl? CN? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
159? ? Cl? CN? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
160? ? Cl? CN? CH 2 3,4, the 5-trimethoxyphenyl
161? ? Cl? CN? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
162? ? Cl? CN? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
163? ? Cl? CN? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
164? ? Cl? CN? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
165? ? Cl? CN? CH 2 3,4, the 5-trimethylphenyl
166? ? Cl? CN? CH 2 2-chloro-3,4, the 5-trimethylphenyl
167? ? Cl? CN? CH 2 2-bromo-3,4, the 5-trimethylphenyl
168? ? Cl? CN? CH 2 2-iodo-3,4, the 5-trimethylphenyl
169? ? Cl? CN? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
170? ? Cl? CN? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
171? ? Cl? CN? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
172? ? Cl? CN? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
173? ? Cl? CN? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
174? ? Cl? CN? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
175? ? Cl? Cl? CH 2 3,4, the 5-trimethoxyphenyl
176? ? Cl? Cl? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
177? ? Cl? Cl? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
178? ? Cl? Cl? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
179? ? Cl? Cl? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
180? ? Cl? Cl? CH 2 3,4, the 5-trimethylphenyl
181? ? Cl? Cl? CH 2 2-chloro-3,4, the 5-trimethylphenyl
182? ? Cl? Cl? CH 2 2-bromo-3,4, the 5-trimethylphenyl
183? ? Cl? Cl? CH 2 2-iodo-3,4, the 5-trimethylphenyl
184? ? Cl? Cl? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
185? ? Cl? Cl? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
186? ? Cl? Cl? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
187? ? Cl? Cl? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
188? ? Cl? Cl? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
189? ? Cl? Cl? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
190? ? Cl? Br? CH 2 3,4, the 5-trimethoxyphenyl
191? ? Cl? Br? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
192? ? Cl? Br? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
193? ? Cl? Br? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
194? ? Cl? Br? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
195? ? Cl? Br? CH 2 3,4, the 5-trimethylphenyl
196? ? Cl? Br? CH 2 2-chloro-3,4, the 5-trimethylphenyl
197? ? Cl? Br? CH 2 2-bromo-3,4, the 5-trimethylphenyl
198? ? Cl? Br? CH 2 2-iodo-3,4, the 5-trimethylphenyl
199? ? Cl? Br? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
200? ? Cl? Br? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
201? ? Cl? Br? CH 2 2-chloro-3,5-dimethoxy-4 '-methylbenzene
? ? ? ? ? Base
202? ? Cl? Br? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
203? ? Cl? Br? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
204? ? Cl? Br? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
205? ? Cl? I? CH 2 3,4, the 5-trimethoxyphenyl
206? ? Cl? I? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
207? ? Cl? I? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
208? ? Cl? I? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
209? ? Cl? I? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
210? ? Cl? I? CH 2 3,4, the 5-trimethylphenyl
211? ? Cl? I? CH 2 2-chloro-3,4, the 5-trimethylphenyl
212? ? Cl? I? CH 2 2-bromo-3,4, the 5-trimethylphenyl
213? ? Cl? I? CH 2 2-iodo-3,4, the 5-trimethylphenyl
214? ? Cl? I? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
215? ? Cl? I? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
216? ? Cl? I? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
217? ? Cl? I? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
218? ? Cl? I? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
219? ? Cl? I? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
220? ? Cl? CH 2- NMe 2 CH 2 3,4, the 5-trimethoxyphenyl
221? ? Cl? CH 2-? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
? ? ? NMe2? ? ?
222? ? Cl? CH 2- NMe 2 CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
223? ? Cl? CH 2- NMe 2 CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
224? ? Cl? CH 2- NMe 2 CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
225? ? Cl? CH 2- NMe 2 CH 2 3,4, the 5-trimethylphenyl
226? ? Cl? CH 2- NMe 2 CH 2 2-chloro-3,4, the 5-trimethylphenyl
227? ? Cl? CH 2- NMe 2 CH 2 2-bromo-3,4, the 5-trimethylphenyl
228? ? Cl? CH 2- NMe 2 CH 2 2-iodo-3,4, the 5-trimethylphenyl
229? ? Cl? CH 2- NMe 2 CH 2 2-fluoro-3,4, the 5-trimethylphenyl
230? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
231? ? Cl? CH 2- NMe 2 CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
232? ? Cl? CH 2- NMe 2 CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
233? ? Cl? CH 2- NMe 2 CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
234? ? Cl? CH 2- NMe 2 CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
235? ? Cl? 3-Py? CH 2 3,4, the 5-trimethoxyphenyl
236? ? Cl? 3-Py? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
237? ? Cl? 3-Py? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
238? ? Cl? 3-Py? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
239? ? Cl? 3-Py? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
240? 7? Cl? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
241? 10? Cl? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
242? ? Cl? H? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
243? 8? Cl? H? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
244? 14? Cl? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
245? 15? Cl? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
246? 9? Cl? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
247? ? Cl? H? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
248? ? Cl? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
249? ? Cl? H? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
250? ? Cl? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
251? ? Cl? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
252? ? Cl? H? CH 2 3,4,5-trimethylammonium-pyridine-2-base
253? ? C1? H? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
254? ? Cl? H? CH 2 4,5,6-trimethoxy pyridine-2-base
255? ? Cl? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
256? ? Cl? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
257? ? Cl? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
258? ? Cl? H? CH 2 3,4,5-trimethoxy-pyridine-2-base
259? ? Cl? H? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
260? ? Cl? H? CH 2 3-bromo-3,4,5-trimethoxy-pyridine-2-base
261? ? Cl? H? CH 2 3-chloro-3,4,5-trimethoxy-pyridine-2-base
262? ? Cl? H? CH 2 4,5,6-trimethylpyridine-2-base
263? ? Cl? H? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
264? ? Cl? H? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
265? ? Cl? H? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
266? ? Cl? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
267? ? Cl? H? CH 2 4,6-dimethyl-5-bromopyridine-3-base
268? ? Cl? H? CH 2 4,6-dimethyl-5-chloropyridine-3-base
269? ? Cl? H? CH 2 5,6-dimethyl-4-bromopyridine-3-base
270? ? Cl? H? CH 2 5,6-dimethyl-4-chloropyridine-3-base
271? ? Cl? H? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
272? ? Cl? H? CH 2 2,6-dimethyl-pyridin-4-yl
273? ? Cl? H? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
274? ? Cl? H? CH 2 2,3,6-trimethoxy-pyridin-4-yl
275? ? Cl? H? CH 2 2,6-dimethyl-3-bromopyridine-4-base
276? ? Cl? H? CH 2 2,6-dimethyl-3-chloropyridine-4-base
277? ? Cl? H? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
278? ? Cl? H? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
279? ? Cl? H? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
280? ? Cl? H? CH 2 2,3,6-trimethoxy-1-oxygen-pyridine-4-base
281? ? Cl? H? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
282? ? Cl? H? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
283? ? Cl? H? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
284? ? Cl? H? CH 2 3,5-dimethyl-4-aminopyridine-2-base
285? 31? Cl? i-Pr? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
286? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
287? ? Cl? i-Pr? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
288? ? Cl? i-Pr? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
289? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-bromopyridine-2-base
290? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
291? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-chloropyridine-2-base
292? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
293? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
294? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
295? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
296? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-thiomethyl-1-oxygen pyrrole
? ? ? ? ? Pyridine-2-base
297? ? Cl? i-Pr? CH 2 3,4,5-trimethylammonium-pyridine-2-base
298? ? Cl? i-Pr? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
299? ? Cl? i-Pr? CH 2 4,5,6-trimethoxy pyridine-2-base
300? ? Cl? i-Pr? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
301? ? Cl? i-Pr? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
302? ? Cl? i-Pr? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
303? ? Cl? i-Pr? CH 2 3,4,5-trimethoxy-pyridine-2-base
304? ? Cl? i-Pr? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
305? ? Cl? i-Pr? CH 2 3-bromo-3,4,5-trimethoxy-pyridine-2-base
306? ? Cl? i-Pr? CH 2 3-chloro-3,4,5-trimethoxy-pyridine-2-base
307? ? Cl? i-Pr? CH 2 4,5,6-trimethylpyridine-2-base
308? ? Cl? i-Pr? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
309? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
310? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
311? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
312? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-bromopyridine-3-base
313? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-chloropyridine-3-base
314? ? Cl? i-Pr? CH 2 5,6-dimethyl-4-bromopyridine-3-base
315? ? Cl? i-Pr? CH 2 5,6-dimethyl-4-chloropyridine-3-base
316? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
317? ? Cl? i-Pr? CH 2 2,6-dimethyl-pyridin-4-yl
318? ? Cl? i-Pr? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
319? ? Cl? i-Pr? CH 2 2,3,6-trimethoxy-pyridin-4-yl
320? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-bromopyridine-4-base
321? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-chloropyridine-4-base
322? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
323? ? Cl? i-Pr? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
324? ? Cl? i-Pr? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
325? ? Cl? i-Pr? CH 2 2,3,6-trimethoxy-1-oxygen-pyridine-4-base
326? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
327? ? Cl? i-Pr? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
328? ? Cl? i-Pr? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
329? ? Cl? i-Pr? CH 2 3,5-dimethyl-4-aminopyridine-2-base
330? 23? Cl? Me? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
331? ? Cl? Me? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
332? 28? Cl? Me? CH 2 3,5-dimethyl-4-bromopyridine-2-base
333? 24? Cl? Me? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
334? 26? Cl? Me? CH 2 3,5-dimethyl-4-chloropyridine-2-base
335? 25? Cl? Me? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
336? ? Cl? Me? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
337? ? Cl? Me? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
338? ? Cl? Me? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-
? ? ? ? ? Base
339? ? Cl? Me? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
340? ? Cl? Me? CH 2 3,4,5-trimethylammonium-pyridine-2-base
341? ? Cl? Me? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
342? ? Cl? Me? CH 2 4,5,6-trimethoxy pyridine-2-base
343? ? Cl? Me? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
344? ? Cl? Me? CH 2 3,4,5-trimethoxy-pyridine-2-base
345? ? Cl? Me? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
346? ? Cl? Me? CH 2 4,5,6-trimethylpyridine-2-base
347? ? Cl? Me? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
348? ? Cl? Me? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
349? ? Cl? Me? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
350? ? Cl? Me? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
351? ? Cl? Me? CH 2 4,6-dimethyl-5-bromopyridine-3-base
352? ? Cl? Me? CH 2 4,6-dimethyl-5-chloropyridine-3-base
353? ? Cl? Me? CH 2 5,6-dimethyl-4-bromopyridine-3-base
354? ? Cl? Me? CH 2 5,6-dimethyl-4-chloropyridine-3-base
355? ? Cl? Me? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
356? ? Cl? Me? CH 2 2,6-dimethyl-pyridin-4-yl
357? ? Cl? Me? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
358? ? Cl? Me? CH 2 2,3,6-trimethoxy-pyridin-4-yl
359? ? Cl? Me? CH 2 2,6-dimethyl-3-bromopyridine-4-base
360? ? Cl? Me? CH 2 2,6-dimethyl-3-chloropyridine-4-base
361? ? Cl? Me? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
362? ? Cl? Me? CH 2 3,5-dimethyl-4-aminopyridine-2-base
363? 29? Cl? Et? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
364? ? Cl? Et? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
365? ? Cl? Et? CH 2 3,5-dimethyl-4-bromopyridine-2-base
366? ? Cl? Et? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
367? 30? Cl? Et? CH 2 3,5-dimethyl-4-chloropyridine-2-base
368? ? Cl? Et? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
369? ? Cl? Et? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
370? ? Cl? Et? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
371? ? Cl? Et? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
372? ? Cl? Et? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
373? ? Cl? Et? CH 2 3,4,5-trimethylammonium-pyridine-2-base
374? ? Cl? Et? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
375? ? Cl? Et? CH 2 4,5,6-trimethoxy pyridine-2-base
376? ? Cl? Et? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
377? ? Cl? Et? CH 2 3,4,5-trimethoxy-pyridine-2-base
378? ? Cl? Et? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
379? ? Cl? Et? CH 2 4,5,6-trimethylpyridine-2-base
380? ? Cl? Et? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
381? ? Cl? Et? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
382? ? Cl? Et? CH 2 4,6-dimethyl-5-methoxypyridine-3-
? ? ? ? ? Base
383? ? Cl? Et? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
384? ? Cl? Et? CH 2 4,6-dimethyl-5-bromopyridine-3-base
385? ? Cl? Et? CH 2 4,6-dimethyl-5-chloropyridine-3-base
386? ? Cl? Et? CH 2 5,6-dimethyl-4-bromopyridine-3-base
387? ? Cl? Et? CH 2 5,6-dimethyl-4-chloropyridine-3-base
388? ? Cl? Et? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
389? ? Cl? Et? CH 2 2,6-dimethyl-pyridin-4-yl
390? ? Cl? Et? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
391? ? Cl? Et? CH 2 2,3,6-trimethoxy-pyridin-4-yl
392? ? Cl? Et? CH 2 2,6-dimethyl-3-bromopyridine-4-base
393? ? Cl? Et? CH 2 2,6-dimethyl-3-chloropyridine-4-base
394? ? Cl? Et? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
395? ? Cl? Et? CH 2 3,5-dimethyl-4-aminopyridine-2-base
396? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
397? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
398? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-bromopyridine-2-base
399? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
400? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-chloropyridine-2-base
401? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
402? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
403? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
404? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
405? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
406? ? Cl? 2-Py? CH 2 3,4,5-trimethylammonium-pyridine-2-base
407? ? Cl? 2-Py? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
408? ? Cl? 2-Py? CH 2 4,5,6-trimethoxy pyridine-2-base
409? ? Cl? 2-Py? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
410? ? Cl? 2-Py? CH 2 3,4,5-trimethoxy-pyridine-2-base
411? ? Cl? 2-Py? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
412? ? Cl? 2-Py? CH 2 4,5,6-trimethylpyridine-2-base
413? ? Cl? 2-Py? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
414? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
415? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
416? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
417? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-bromopyridine-3-base
418? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-chloropyridine-3-base
419? ? Cl? 2-Py? CH 2 5,6-dimethyl-4-bromopyridine-3-base
420? ? Cl? 2-Py? CH 2 5,6-dimethyl-4-chloropyridine-3-base
421? ? Cl? 2-Py? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
422? ? Cl? 2-Py? CH 2 2,6-dimethyl-pyridin-4-yl
423? ? Cl? 2-Py? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
424? ? Cl? 2-Py? CH 2 2,3,6-trimethoxy-pyridin-4-yl
425? ? Cl? 2-Py? CH 2 2,6-dimethyl-3-bromopyridine-4-base
426? ? Cl? 2-Py? CH 2 2,6-dimethyl-3-chloropyridine-4-base
427? ? Cl? 2-Py? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
428? ? Cl? 2-Py? CH 2 3,5-dimethyl-4-aminopyridine-2-base
429? 32? Cl? Ph? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
430? ? Cl? Ph? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
431? 34? Cl? Ph? CH 2 3,5-dimethyl-4-bromopyridine-2-base
432? ? Cl? Ph? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
433? 33? Cl? Ph? CH 2 3,5-dimethyl-4-chloropyridine-2-base
434? 35? Cl? Ph? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
435? ? Cl? Ph? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
436? ? Cl? Ph? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
437? ? Cl? Ph? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
438? ? Cl? Ph? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
439? ? Cl? Ph? CH 2 3,4,5-trimethylammonium-pyridine-2-base
440? ? Cl? Ph? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
441? ? Cl? Ph? CH 2 4,5,6-trimethoxy pyridine-2-base
442? ? Cl? Ph? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
443? ? Cl? Ph? CH 2 3,4,5-trimethoxy-pyridine-2-base
444? ? Cl? Ph? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
445? ? Cl? Ph? CH 2 4,5,6-trimethylpyridine-2-base
446? ? Cl? Ph? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
447? ? Cl? Ph? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
448? ? Cl? Ph? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
449? ? Cl? Ph? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
450? ? Cl? Ph? CH 2 4,6-dimethyl-5-bromopyridine-3-base
451? ? Cl? Ph? CH 2 4,6-dimethyl-5-chloropyridine-3-base
452? ? Cl? Ph? CH 2 5,6-dimethyl-4-bromopyridine-3-base
453? ? Cl? Ph? CH 2 5,6-dimethyl-4-chloropyridine-3-base
454? ? Cl? Ph? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
455? ? Cl? Ph? CH 2 2,6-dimethyl-pyridin-4-yl
456? ? Cl? Ph? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
457? ? Cl? Ph? CH 2 2,3,6-trimethoxy-pyridin-4-yl
458? ? Cl? Ph? CH 2 2,6-dimethyl-3-bromopyridine-4-base
459? ? Cl? Ph? CH 2 2,6-dimethyl-3-chloropyridine-4-base
460? ? Cl? Ph? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
461? ? Cl? Ph? CH 2 3,5-dimethyl-4-aminopyridine-2-base
462? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
463? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
464? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-bromopyridine-2-base
465? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
466? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-chloropyridine-2-base
467? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
468? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
469? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-
? ? ? ? ? Base
470? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
471? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
472? ? Cl? 3-Py? CH 2 3,4,5-trimethylammonium-pyridine-2-base
473? ? Cl? 3-Py? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
474? ? Cl? 3-Py? CH 2 4,5,6-trimethoxy pyridine-2-base
475? ? Cl? 3-Py? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
476? ? Cl? 3-Py? CH 2 3,4,5-trimethoxy-pyridine-2-base
477? ? Cl? 3-Py? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
478? ? Cl? 3-Py? CH 2 4,5,6-trimethylpyridine-2-base
479? ? Cl? 3-Py? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
480? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-methoxypyridine-2-base
481? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
482? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
483? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-bromopyridine-3-base
484? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-chloropyridine-3-base
485? ? Cl? 3-Py? CH 2 5,6-dimethyl-4-bromopyridine-3-base
486? ? Cl? 3-Py? CH 2 5,6-dimethyl-4-chloropyridine-3-base
487? ? Cl? 3-Py? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
488? ? Cl? 3-Py? CH 2 2,6-dimethyl-pyridin-4-yl
489? ? Cl? 3-Py? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
490? ? Cl? 3-Py? CH 2 2,3,6-trimethoxy-pyridin-4-yl
491? ? Cl? 3-Py? CH 2 2,6-dimethyl-3-bromopyridine-4-base
492? ? Cl? 3-Py? CH 2 2,6-dimethyl-3-chloropyridine-4-base
493? ? Cl? 3-Py? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
494? ? Cl? 3-Py? CH 2 3,5-dimethyl-4-aminopyridine-2-base
495? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-methoxypyridine-2-base
496? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
497? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-bromopyridine-2-base
498? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
499? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-chloropyridine-2-base
500? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
501? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-iodine pyridine-2-base
502? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
503? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
504? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
505? ? Cl? CH 2- NMe 2 CH 2 3,4,5-trimethylammonium-pyridine-2-base
506? ? Cl? CH 2- NMe 2 CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
507? ? Cl? CH 2- NMe 2 CH 2 4,5,6-trimethoxy pyridine-2-base
508? ? Cl? CH 2- NMe 2 CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
509? ? Cl? CH 2- NMe 2 CH 2 3,4,5-trimethoxy-pyridine-2-base
510? ? Cl? CH 2- NMe 2 CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
511? ? Cl? CH 2- NMe 2 CH 2 4,5,6-trimethylpyridine-2-base
512? ? Cl? CH 2- NMe 2 CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
513? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-methoxypyridine-2-base
514? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-methoxypyridine-3-base
515? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
516? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-bromopyridine-3-base
517? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-chloropyridine-3-base
518? ? Cl? CH 2- NMe 2 CH 2 5,6-dimethyl-4-bromopyridine-3-base
519? ? Cl? CH 2- NMe 2 CH 2 5,6-dimethyl-4-chloropyridine-3-base
520? ? Cl? CH 2- NMe 2 CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
521? ? Cl? CH 2- NMe 2 CH 2 2,6-dimethyl-pyridin-4-yl
522? ? Cl? CH 2-? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
? ? ? NMe 2 ? ?
523? ? Cl? CH 2- NMe 2 CH 2 2,3,6-trimethoxy-pyridin-4-yl
524? ? Cl? CH 2- NMe 2 CH2? 2,6-dimethyl-3-bromopyridine-4-base
525? ? Cl? CH 2- NMe 2 CH 2 2,6-dimethyl-3-chloropyridine-4-base
526? ? Cl? CH 2- NMe 2 CH 2 4,6-dimethyl-5-iodine pyridine-3-base
527? ? Cl? CH 2- NMe 2 CH 2 3,5-dimethyl-4-aminopyridine-2-base
528? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-methoxypyridine-2-base
529? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
530? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-bromopyridine-2-base
531? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
532? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-chloropyridine-2-base
533? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
534? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-iodine pyridine-2-base
536? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
537? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
538? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
539? ? Cl? The 2-furyl CH 2 3,4,5-trimethylammonium-pyridine-2-base
540? ? Cl? The 2-furyl CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
541? ? Cl? The 2-furyl CH 2 4,5,6-trimethoxy pyridine-2-base
542? ? Cl? The 2-furyl CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
543? ? Cl? The 2-furyl CH 2 3,4,5-trimethoxy-pyridine-2-base
544? ? Cl? The 2-furyl CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
545? ? Cl? The 2-furyl CH 2 4,5,6-trimethylpyridine-2-base
546? ? Cl? The 2-furyl CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
547? ? Cl? The 2-furyl CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
548? ? Cl? The 2-furyl CH 2 4,6-dimethyl-5-methoxypyridine-3-base
549? ? Cl? The 2-furyl CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
550? ? Cl? The 2-furyl CH 2 4,6-dimethyl-5-bromopyridine-3-base
551? ? Cl? The 2-furyl CH 2 4,6-dimethyl-5-chloropyridine-3-base
552? ? Cl? The 2-furan CH 2 5,6-dimethyl-4-bromopyridine-3-base
? ? ? The base of muttering ? ?
553? ? Cl? The 2-furyl CH 2 5,6-dimethyl-4-chloropyridine-3-base
554? ? Cl? The 2-furyl CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
555? ? Cl? The 2-furyl CH 2 2,6-dimethyl-pyridin-4-yl
556? ? Cl? The 2-furyl CH 2 2,3,6-trimethylammonium-pyridin-4-yl
557? ? Cl? The 2-furyl CH 2 2,3,6-trimethoxy-pyridin-4-yl
558? ? Cl? The 2-furyl CH 2 2,6-dimethyl-3-bromopyridine-4-base
559? ? Cl? The 2-furyl CH 2 2,6-dimethyl-3-chloropyridine-4-base
560? ? Cl? The 2-furyl CH 2 3,5-dimethyl-4-aminopyridine-2-base
561? ? Cl? Cl? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
562? ? Cl? Cl? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
563? ? Cl? Cl? CH 2 3,5-dimethyl-4-bromopyridine-2-base
564? ? Cl? Cl? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
565? ? Cl? Cl? CH 2 3,5-dimethyl-4-chloropyridine-2-base
566? ? Cl? Cl? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
567? ? Cl? Cl? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
568? ? Cl? Cl? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-
? ? ? ? ? Base
569? ? Cl? Cl? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
570? ? Cl? Cl? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
571? ? Cl? Cl? CH 2 3,4,5-trimethylammonium-pyridine-2-base
572? ? Cl? Cl? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
573? ? Cl? Cl? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
574? ? Cl? Cl? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
575? ? Cl? Cl? CH 2 3,5-dimethyl-4-aminopyridine-2-base
576? ? Cl? Br? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
577? ? Cl? Br? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
578? ? Cl? Br? CH 2 3,5-dimethyl-4-bromopyridine-2-base
579? ? Br? Br? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
580? ? Cl? Br? CH 2 3,5-dimethyl-4-chloropyridine-2-base
581? ? Br? Br? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
582? ? Cl? Br? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
583? ? Br? Br? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
584? ? Cl? B r CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
585? ? Br? Br? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
586? ? Cl? Br? CH 2 3,4,5-trimethylammonium-pyridine-2-base
587? ? Br? Br? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
588? ? Cl? Br? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
589? ? Cl? Br? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
590? ? Cl? Br? CH 2 3,5-dimethyl-4-aminopyridine-2-base
591? ? Cl? I? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
592? ? Cl? I? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
593? ? Cl? I? CH 2 3,5-dimethyl-4-bromopyridine-2-base
594? ? Cl? I? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
595? ? Cl? I? CH 2 3,5-dimethyl-4-chloropyridine-2-base
596? ? Cl? I? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
597? ? Cl? I? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
598? ? Cl? I? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
599? ? Cl? I? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
600? ? Cl? I? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
601? ? Cl? I? CH 2 3,4,5-trimethylammonium-pyridine-2-base
602? ? Cl? I? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
603? ? Cl? I? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
604? ? Cl? I? CH 2 4,6-dimethyl-5-methoxyl group-1-oxygen pyrrole
? ? ? ? ? Pyridine-3-base
605? ? Cl? I? CH 2 3,5-dimethyl-4-aminopyridine-2-base
606? ? Cl? CN? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
607? ? Cl? CN? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
608? ? Cl? CN? CH 2 3,5-dimethyl-4-bromopyridine-2-base
609? ? Cl? CN? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
610? ? Cl? CN? CH 2 3,5-dimethyl-4-chloropyridine-2-base
611? ? Cl? CN? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
612? ? Cl? CN? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
613? ? Cl? CN? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
614? ? Cl? CN? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
615? ? Cl? CN? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
616? ? Cl? CN? CH 2 3,4,5-trimethylammonium-pyridine-2-base
617? ? Cl? CN? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
618? ? Cl? CN? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
619? ? Cl? CN? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
620? ? Cl? CN? CH 2 3,5-dimethyl-4-aminopyridine-2-base
621? ? Cl? H? C(O)? 3,5-dimethyl-4-methoxypyridine-2-base
622? ? Cl? H? C(O)? 3,5-dimethyl-4-methoxyl group-1-oxygen pyrrole
? ? ? ? ? Pyridine-2-base
623? ? 61? H? C(O)? 3,5-dimethyl-4-bromopyridine-2-base
624? ? Cl? H? C(O)? 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
625? ? Cl? H? C(O)? 3,5-dimethyl-4-chloropyridine-2-base
626? ? Cl? H? C(O)? 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
627? ? Cl? H? C(O)? 3,5-dimethyl-4-iodine pyridine-2-base
628? ? Cl? H? C(O)? 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
629? ? Cl? H? C(O)? 3,5-dimethyl-4-thiomethyl-pyridine-2-base
630? ? Cl? H? C(O)? 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
631? ? Cl? H? C(O)? 3,4,5-trimethylammonium-pyridine-2-base
632? ? Cl? H? C(O)? 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
633? ? Cl? H? C(O)? 4,6-dimethyl-5-methoxypyridine-3-base
634? ? Cl? H? C(O)? 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
635? ? Cl? H? C(O)? 3,5-dimethyl-4-aminopyridine-2-base
636? ? Cl? H? S(O)? 3,5-dimethyl-4-methoxypyridine-2-base
637? ? Cl? H? S(O)? 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
638? ? Cl? H? S(O)? 3,5-dimethyl-4-bromopyridine-2-base
639? ? Cl? H? S(O)? 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
640? ? Cl? H? S(O)? 3,5-dimethyl-4-chloropyridine-2-base
641? ? Cl? H? S(O)? 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
642? ? Cl? H? S(O)? 3,5-dimethyl-4-iodine pyridine-2-base
643? ? Cl? H? S(O)? 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
644? ? Cl? H? S(O)? 3,5-dimethyl-4-thiomethyl-pyridine-2-base
645? ? Cl? H? S(O)? 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
646? ? Cl? Br? S(O)? 3,4,5-trimethylammonium-pyridine-2-base
647? ? Cl? H? S(O)? 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
648? ? Cl? Br? S(O)? 4,6-dimethyl-5-methoxypyridine-3-base
649? ? Cl? H? S(O)? 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
650? ? Cl? H? SO 2 3,5-dimethyl-4-methoxypyridine-2-base
651? ? Cl? H? SO 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
652? ? Cl? H? SO 2 3,5-dimethyl-4-bromopyridine-2-base
653? ? Cl? H? SO 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
654? ? Cl? Br? SO 2 3,5-dimethyl-4-chloropyridine-2-base
655? ? Cl? H? SO 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
656? ? Cl? H? SO 2 3,5-dimethyl-4-iodine pyridine-2-base
657? ? Cl? H? SO 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
658? ? Cl? H? SO 2 3,5-dimethyl-4-thiomethyl-pyridine-2-
? ? ? ? ? Base
659? ? Cl? H? SO 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
660? ? Cl? H? SO 2 3,4,5-trimethylammonium-pyridine-2-base
661? ? Cl? H? SO 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
662? ? Cl? H? SO 2 4,6-dimethyl-5-methoxypyridine-3-base
663? ? Cl? H? SO 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
664? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-methoxypyridine-2-base
665? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
666? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-bromopyridine-2-base
667? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
668? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-chloropyridine-2-base
669? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
670? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-iodine pyridine-2-base
671? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
672? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-thiomethyl-pyridine-2-base
673? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
674? ? Cl? i-Pr? C(O)? 3,4,5-trimethylammonium-pyridine-2-base
675? ? Cl? i-Pr? C(O)? 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
676? ? Cl? i-Pr? C(O)? 4,6-dimethyl-5-methoxypyridine-3-
? ? ? ? ? Base
677? ? Cl? i-Pr? C(O)? 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
678? ? Cl? i-Pr? C(O)? 3,5-dimethyl-4-aminopyridine-2-base
679? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-methoxypyridine-2-base
680? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
681? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-bromopyridine-2-base
682? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
683? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-chloropyridine-2-base
684? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
685? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-iodine pyridine-2-base
686? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
687? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-thiomethyl-pyridine-2-base
688? ? Cl? i-Pr? S(O)? 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
689? ? Cl? i-Pr? S(O)? 3,4,5-trimethylammonium-pyridine-2-base
690? ? Cl? i-Pr? S(O)? 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
691? ? Cl? i-Pr? S(O)? 4,6-dimethyl-5-methoxypyridine-3-base
692? ? Cl? i-Pr? S(O)? 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
693? ? Cl? i-Pr? SO2? 3,5-dimethyl-4-methoxypyridine-2-base
694? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
695? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-bromopyridine-2-base
696? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
697? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-chloropyridine-2-base
698? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
699? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-iodine pyridine-2-base
700? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
701? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
702? ? Cl? i-Pr? SO 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
703? ? Cl? i-Pr? SO 2 3,4,5-trimethylammonium-pyridine-2-base
704? ? Cl? i-Pr? SO 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
705? ? Cl? i-Pr? SO 2 4,6-dimethyl-5-methoxypyridine-3-base
706? ? Cl? i-Pr? SO 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
707? ? Cl? H? C(O)? 3,4, the 5-trimethoxyphenyl
708? ? Cl? H? C(O)? 2-chloro-3,4, the 5-trimethoxyphenyl
709? ? Cl? H? C(O)? 2-bromo-3,4, the 5-trimethoxyphenyl
710? ? Cl? H? C(O)? 3,5-dimethyl-4-p-methoxy-phenyl
711? ? Cl? H? C(O)? 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
712? ? Cl? H? C(O)? 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
713? ? Cl? H? SO 2 3,4, the 5-trimethoxyphenyl
714? ? Cl? H? SO 2 2-chloro-3,4, the 5-trimethoxyphenyl
715? ? Cl? H? SO 2 2-bromo-3,4, the 5-trimethoxyphenyl
716? ? Cl? H? SO 2 3,5-dimethyl-4-p-methoxy-phenyl
717? ? Cl? H? SO 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
718? ? Cl? H? SO 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
719? ? Br? H? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
720? ? Br? H? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
721? ? Br? H? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
722? ? Br? H? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
723? ? Br? H? CH 2 3,5-dimethyl-4-bromopyridine-2-base
724? ? Br? H? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
725? ? Br? H? CH 2 3,5-dimethyl-4-chloropyridine-2-base
726? ? Br? H? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
727? ? Br? H? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
728? ? Br? H? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
729? ? Br? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
730? ? Br? H? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
731? ? Br? H? CH 2 3,4,5-trimethylammonium-pyridine-2-base
732? ? Br? H? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
733? ? Br? H? CH 2 4,5,6-trimethoxy pyridine-2-base
734? ? Br? H? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
735? ? Br? H? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
736? ? Br? H? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
737? ? Br? H? CH 2 3,4,5-trimethoxy-pyridine-2-base
738? ? Br? H? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
739? ? Br? H? CH 2 3-bromo-3,4,5-trimethoxy-pyridine-2-base
740? ? Br? H? CH 2 3-chloro-3,4,5-trimethoxy-pyridine-2-base
741? ? Br? H? CH 2 4,5,6-trimethylammonium-pyridine-2-base
742? ? Br? H? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
743? ? Br? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
744? ? Br? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-3-base
745? ? Br? H? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
746? ? Br? H? CH 2 4,6-dimethyl-5-bromopyridine-3-base
747? ? Br? H? CH 2 4,6-dimethyl-5-chloropyridine-3-base
748? ? Br? H? CH 2 5,6-dimethyl-4-bromopyridine-3-base
749? ? Br? H? CH 2 5,6-dimethyl-4-chloropyridine-3-base
750? ? Br? H? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
751? ? Br? H? CH 2 2,6-dimethyl-pyridin-4-yl
752? ? Br? H? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
753? ? Br? H? CH 2 2,3,6-trimethoxy-pyridin-4-yl
754? ? Br? H? CH 2 2,6-dimethyl-3-bromopyridine-4-base
755? ? Br? H? CH 2 2,6-dimethyl-3-chloropyridine-4-base
756? ? Br? H? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
757? ? Br? H? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
758? ? Br? H? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
759? ? Br? H? CH 2 2,3,6-trimethoxy-1-oxygen-pyridine-4-base
760? ? Br? H? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
761? ? Br? H? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
762? ? Br? H? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
763? ? Br? H? CH 2 3,5-dimethyl-4-aminopyridine-2-base
764? ? Br? i-Pr? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
765? ? Br? i-Pr? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
766? ? Br? i-Pr? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
767? ? Br? i-Pr? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
768? ? Br? i-Pr? CH 2 3,5-dimethyl-4-bromopyridine-2-base
769? ? Br? i-Pr? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
770? ? Br? i-Pr? CH 2 3,5-dimethyl-4-chloropyridine-2-base
771? ? Br? i-Pr? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
772? ? Br? i-Pr? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
773? ? Br? i-Pr? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
774? ? Br? i-Pr? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
775? ? Br? i-Pr? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
776? ? Br? i-Pr? CH 2 3,4,5-trimethylammonium-pyridine-2-base
777? ? Br? i-Pr? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
778? ? Br? i-Pr? CH 2 4,5,6-trimethoxy pyridine-2-base
779? ? Br? i-Pr? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
780? ? Br? i-Pr? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
781? ? Br? i-Pr? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
782? ? Br? i-Pr? CH 2 3,4,5-trimethoxy-pyridine-2-base
783? ? Br? i-Pr? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
784? ? Br? i-Pr? CH 2 3-bromo-3,4,5-trimethoxy-pyridine-2-base
785? ? Br? i-Pr? CH 2 3-chloro-3,4,5-trimethoxy-pyridine-2-base
786? ? Br? i-Pr? CH 2 4,5,6-trimethylpyridine-2-base
787? ? Br? i-Pr? CH 2 4,5,6-trimethylammonium-pyridine 1-oxide-2-base
788? ? Br? i-Pr? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
789? ? Br? i-Pr? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-3-base
790? ? Br? i-Pr? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
791? ? Br? i-Pr? CH 2 4,6-dimethyl-5-bromopyridine-3-base
792? ? Br? i-Pr? CH 2 4,6-dimethyl-5-chloropyridine-3-base
793? ? Br? i-Pr? CH 2 5,6-dimethyl-4-bromopyridine-3-base
794? ? Br? i-Pr? CH 2 5,6-dimethyl-4-chloropyridine-3-base
795? ? Br? i-Pr? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
796? ? Br? i-Pr? CH 2 2,6-dimethyl-pyridin-4-yl
797? ? Br? i-Pr? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
798? ? Br? i-Pr? CH 2 2,3,6-trimethoxy-pyridin-4-yl
799? ? Br? i-Pr? CH 2 2,6-dimethyl-3-bromopyridine-4-base
800? ? Br? i-Pr? CH 2 2,6-dimethyl-3-chloropyridine-4-base
801? ? Br? i-Pr? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
802? ? Br? i-Pr? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
803? ? Br? i-Pr? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
804? ? Br? i-Pr? CH 2 2,3,6-trimethoxy-1-oxygen-pyridine-4-base
805? ? Br? i-Pr? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
806? ? Br? i-Pr? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
807? ? Br? i-Pr? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
808? ? Br? i-Pr? CH 2 3,5-dimethyl-4-aminopyridine-2-base
809? ? Br? Ph? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
810? ? Br? Ph? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
811? ? Br? Ph? CH 2 3,5-dimethyl-4-bromopyridine-2-base
812? ? Br? Ph? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
813? ? Br? Ph? CH 2 3,5-dimethyl-4-chloropyridine-2-base
814? ? Br? Ph? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-
? ? ? ? ? Base
815? ? Br? Ph? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
816? ? Br? Ph? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
817? ? Br? Ph? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
818? ? Br? Ph? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
819? ? Br? Ph? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
820? ? Br? Ph? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
821? ? Br? Ph? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-3-base
822? ? Br? Ph? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
823? ? Br? Et? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
824? ? Br? Et? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
825? ? Br? Et? CH 2 3,5-dimethyl-4-bromopyridine-2-base
826? ? Br? Et? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
827? ? Br? Et? CH 2 3,5-dimethyl-4-chloropyridine-2-base
828? ? Br? Et? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
829? ? Br? Et? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
830? ? Br? Et? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
831? ? Br? Et? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
832? ? Br? Et? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
833? ? Br? Et? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
834? ? Br? Et? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
835? ? Br? Et? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
836? ? Br? Et? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
837? ? Br? Me? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
838? ? Br? Me? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
839? ? Br? Me? CH 2 3,5-dimethyl-4-bromopyridine-2-base
840? ? Br? Me? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
841? ? Br? Me? CH 2 3,5-dimethyl-4-chloropyridine-2-base
842? ? Br? Me? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
843? ? Br? Me? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
844? ? Br? Me? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
845? ? Br? Me? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
846? ? Br? Me? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
847? ? Br? Me? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
848? ? Br? Me? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
849? ? Br? Me? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
850? ? Br? Me? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
851? ? Br? 2-Py? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
852? ? Br? 2-Py? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
853? ? Br? 2-Py? CH 2 3,5-dimethyl-4-bromopyridine-2-base
854? ? Br? 2-Py? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
855? ? Br? 2-Py? CH 2 3,5-dimethyl-4-chloropyridine-2-base
856? ? Br? 2-Py? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
857? ? Br? 2-Py? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
858? ? Br? 2-Py? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
859? ? Br? 2-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
860? ? Br? 2-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
861? ? Br? 2-Py? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
862? ? Br? 2-Py? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
863? ? Br? 2-Py? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
864? ? Br? 2-Py? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
865? ? Br? 3-Py? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
866? ? Br? 3-Py? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
867? ? Br? 3-Py? CH 2 3,5-dimethyl-4-bromopyridine-2-base
868? ? Br? 3-Py? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
869? ? Br? 3-Py? CH 2 3,5-dimethyl-4-chloropyridine-2-base
870? ? Br? 3-Py? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
871? ? Br? 3-Py? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
872? ? Br? 3-Py? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
873? ? Br? 3-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine-2-base
874? ? Br? 3-Py? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
875? ? Br? 3-Py? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
876? ? Br? 3-Py? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
877? ? Br? 3-Py? CH 2 4,6-dimethyl-5-methoxypyridine-3-base
878? ? Br? 3-Py? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
Compound useful in the table 3 is: 1,2,3,16,17,18,27,28,47,48,62,63,77,78,92,93,97,98,129,130,242,243,245,246,247,248,249,250,251,252,253,267,268,287,288,289,290,291,292,293,294,295,296,297,298,312,313,332,333,334,335,336,337,338,339,351,352,365,366,367,368,369,370,384,385,398,399,400,401,417,418,431,432,433,434,435,436,437,438,439,440,450,451,464,465,466,466,467,468,469,470,471,483,484,497,498,530,531,550,551,563,564,575,576,578,579,590,591,593,594,605,606,608,609,620,621,721,722,725,726,727,728,729,730,746,747,766,767,791,792,811,812,823,824,825,826,839,840,853,854,867 and 868, preferred compound is 242,243,245,246,247,248,267,268,287,288,312,313,332,333,334,335,336,337,338,339,365,369,398,417,431,432,433,434,435,436,437,438,450,451,464,465,483 and 484.
The example compound of table 4: formula IV
Figure GSA00000083249101831
No.? Embodiment R 1 R 4 R 5
1? 5? Cl? CH 2 3,4, the 5-trimethoxyphenyl
2? 6? Cl? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
3? 8? Cl? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
4? 10? Cl? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
5? ? Cl? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
6? ? Cl? CH 2 3,4, the 5-trimethylphenyl
7? ? Cl? CH 2 2-chloro-3,4, the 5-trimethylphenyl
8? ? Cl? CH 2 2-bromo-3,4, the 5-trimethylphenyl
9? ? Cl? CH 2 2-iodo-3,4, the 5-trimethylphenyl
10? ? Cl? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
11? ? Cl? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
12? ? Cl? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
13? ? Cl? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
14? ? Cl? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
15? ? Cl? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
16? ? Cl? CH 2 3,5-two chloro-4-aminomethyl phenyls
17? ? Cl? CH 2 2,3,5-three chloro-4-aminomethyl phenyls
18? ? Cl? CH 2 2-bromo-3,5-two chloro-4-aminomethyl phenyls
19? ? Cl? CH 2 2-iodo-3,5-two chloro-4-aminomethyl phenyls
20? ? Cl? CH 2 2-fluoro-3,5-two chloro-4-aminomethyl phenyls
21? ? Cl? CH 2 3,5-two bromo-4-aminomethyl phenyls
22? ? Cl? CH 2 2-chloro-3,5-two bromo-4-aminomethyl phenyls
23? ? Cl? CH 2 2,3,5-three bromo-4-methyl phenyl phenyls
24? ? Cl? CH 2 2-iodo-3,5-two bromo-4-aminomethyl phenyls
25? ? Cl? CH 2 2-fluoro-3,5-two bromo-4-aminomethyl phenyls
26? ? Cl? CH 2 3,5-two chloro-4-p-methoxy-phenyls
27? ? Cl? CH 2 2,3,5-three chloro-4-p-methoxy-phenyls
28? ? Cl? CH 2 2-bromo-3,5-two chloro-4-p-methoxy-phenyls
29? ? Cl? CH 2 2-iodo-3,5-two chloro-4-p-methoxy-phenyls
30? ? Cl? CH 2 2-fluoro-3,5-two chloro-4-p-methoxy-phenyls
31? ? Cl? CH 2 3,5-two bromo-4-p-methoxy-phenyls
32? ? Cl? CH 2 2-chloro-3,5-two bromo-4-p-methoxy-phenyls
33? ? Cl? CH 2 2,3,5-three bromo-4-p-methoxy-phenyls
34? ? Cl? CH 2 2-iodo-3,5-two bromo-4-p-methoxy-phenyls
35? ? Cl? CH 2 2-fluoro-3,5-two bromo-4-p-methoxy-phenyls
36? ? Cl? CH 2 3-chloro-5-bromo-4-aminomethyl phenyl
37? ? Cl? CH 2 2,3-two chloro-5-bromo-4-aminomethyl phenyls
38? ? Cl? CH 2 2,5-two bromo-3-chloro-4-aminomethyl phenyls
39? ? Cl? CH 2 2-iodo-3-chloro-5-bromo-4-aminomethyl phenyl
40? ? Cl? CH 2 2-fluoro-3-chloro-5-bromo-4-aminomethyl phenyl
41? ? Cl? CH 2 3-chloro-5-bromo-4-p-methoxy-phenyl phenyl
42? ? Cl? CH 2 2,3-two chloro-5-bromo-4-p-methoxy-phenyls
43? ? Cl? CH 2 2,5-two bromo-3-chloro-4-p-methoxy-phenyls
44? ? Cl? CH 2 2-iodo-3-chloro-5-bromo-4-p-methoxy-phenyl
45? ? Cl? CH 2 2-fluoro-3-chloro-5-bromo-4-p-methoxy-phenyl
46? ? Cl? CH 2 3-bromo-5-chloro-4-aminomethyl phenyl
47? ? Cl? CH 2 2,5-two chloro-3-bromo-4-aminomethyl phenyls
48? ? Cl? CH 2 2,3-two bromo-5-chloro-4-aminomethyl phenyls
49? ? Cl? CH 2 2-iodo-3-bromo-5-chloro-4-aminomethyl phenyl
50? ? Cl? CH 2 2-fluoro-3-bromo-5-chloro-4-aminomethyl phenyl
51? ? Cl? CH 2 3-bromo-5-chloro-4-p-methoxy-phenyl
52? ? Cl? CH 2 2,5-two chloro-3-bromo-4-p-methoxy-phenyls
53? ? Cl? CH 2 2,3-two bromo-5-chloro-4-p-methoxy-phenyls
54? ? Cl? CH 2 2-iodo-3-bromo-5-chloro-4-p-methoxy-phenyl
55? ? Cl? CH 2 2-fluoro-3-bromo-5-chloro-4-p-methoxy-phenyl
56? ? Cl? CH 2 3,5-dimethoxy-4 '-trifluoromethyl
57? ? Cl? CH 2 2-chloro-3,5-dimethoxy-4 '-trifluoromethyl
58? ? Cl? CH 2 2-bromo-3,5-dimethoxy-4 '-trifluoromethyl
59? ? Cl? CH 2 2-iodo-3,5-dimethoxy-4 '-trifluoromethyl
60? ? Cl? CH 2 2-fluoro-3,5-dimethoxy-4 '-trifluoromethyl
61? ? Cl? CH 2 3,5-two bromo-4-Trifluoromethoxyphen-ls
62? ? Cl? CH 2 2-chloro-3,5-two bromo-4-Trifluoromethoxyphen-ls
63? ? Cl? CH 2 2,3,5-three bromo-4-Trifluoromethoxyphen-ls
64? ? Cl? CH 2 2-iodo-3,5-two bromo-4-Trifluoromethoxyphen-ls
65? ? Cl? CH 2 2-fluoro-3,5-two bromo-4-Trifluoromethoxyphen-ls
66? ? Cl? CH 2 3,5-dimethyl-4-p-methoxy-phenyl
67? ? Cl? CH 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
68? ? Cl? CH 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
69? ? Cl? CH 2 2-iodo-3,5-dimethyl-4-p-methoxy-phenyl
70? ? Cl? CH 2 2-fluoro-3,5-dimethyl-4-p-methoxy-phenyl
71? ? Cl? CH 2 3,5-dimethyl-4-bromophenyl
72? ? Cl? CH 2 2-chloro-3,5-dimethyl-4-bromophenyl
73? ? Cl? CH 2 2,4-two bromo-3,5-3,5-dimethylphenyl
74? ? Cl? CH 2 2-iodo-3,5-dimethyl-4-bromophenyl
75? ? Cl? CH 2 2-fluoro-3,5-dimethyl-4-bromophenyl
76? ? Cl? CH 2 3,5-dimethyl-4-chloro-phenyl-
77? ? Cl? CH 2 2,4-two chloro-3,5-3,5-dimethylphenyl
78? ? Cl? CH2? 2-bromo-3,5-dimethyl-4-chloro-phenyl-
79? ? Cl? CH 2 2-iodo-3,5-dimethyl-4-chloro-phenyl-
80? ? Cl? CH 2 2-fluoro-3,5-dimethyl-4-chloro-phenyl-
81? ? Br? CH 2 3,4, the 5-trimethoxyphenyl
82? ? Br? CH 2 2-chloro-3,4, the 5-trimethoxyphenyl
83? ? Br? CH 2 2-bromo-3,4, the 5-trimethoxyphenyl
84? ? Br? CH 2 2-iodo-3,4, the 5-trimethoxyphenyl
85? ? Br? CH 2 2-fluoro-3,4, the 5-trimethoxyphenyl
86? ? Br? CH 2 3,4, the 5-trimethylphenyl
87? ? Br? CH 2 2-chloro-3,4, the 5-trimethylphenyl
88? ? Br? CH 2 2-bromo-3,4, the 5-trimethylphenyl
89? ? Br? CH 2 2-iodo-3,4, the 5-trimethylphenyl
90? ? Br? CH 2 2-fluoro-3,4, the 5-trimethylphenyl
91? ? Br? CH 2 3,5-dimethoxy-4 '-aminomethyl phenyl
92? ? Br? CH 2 2-chloro-3,5-dimethoxy-4 '-aminomethyl phenyl
93? ? Br? CH 2 2-bromo-3,5-dimethoxy-4 '-aminomethyl phenyl
94? ? Br? CH 2 2-iodo-3,5-dimethoxy-4 '-aminomethyl phenyl
95? ? Br? CH 2 2-fluoro-3,5-dimethoxy-4 '-aminomethyl phenyl
96? ? Br? CH 2 3,5-two chloro-4-aminomethyl phenyls
97? ? Br? CH 2 2,3,5-three chloro-4-aminomethyl phenyls
98? ? Br? CH 2 2-bromo-3,5-two chloro-4-aminomethyl phenyls
99? ? Br? CH 2 2-iodo-3,5-two chloro-4-aminomethyl phenyls
100? ? Br? CH 2 2-fluoro-3,5-two chloro-4-aminomethyl phenyls
101? ? Br? CH 2 3,5-two bromo-4-aminomethyl phenyls
102? ? Br? CH 2 2-chloro-3,5-two bromo-4-aminomethyl phenyls
103? ? Br? CH 2 2,3,5-three bromo-4-methyl phenyl phenyls
104? ? Br? CH 2 2-iodo-3,5-two bromo-4-aminomethyl phenyls
105? ? Br? CH 2 2-fluoro-3,5-two bromo-4-aminomethyl phenyls
106? ? Br? CH 2 3,5-two chloro-4-p-methoxy-phenyls
107? ? Br? CH 2 2,3,5-three chloro-4-p-methoxy-phenyls
108? ? Br? CH 2 2-bromo-3,5-two chloro-4-p-methoxy-phenyls
109? ? Br? CH 2 2-iodo-3,5-two chloro-4-p-methoxy-phenyls
110? ? Br? CH 2 2-fluoro-3,5-two chloro-4-p-methoxy-phenyls
111? ? Br? CH 2 3,5-two bromo-4-p-methoxy-phenyls
112? ? Br? CH 2 2-chloro-3,5-two bromo-4-p-methoxy-phenyls
113? ? Br? CH 2 2,3,5-three bromo-4-p-methoxy-phenyls
114? ? Br? CH 2 2-iodo-3,5-two bromo-4-p-methoxy-phenyls
115? ? Br? CH 2 2-fluoro-3,5-two bromo-4-p-methoxy-phenyls
116? ? Br? CH 2 3-chloro-5-bromo-4-aminomethyl phenyl
117? ? Br? CH 2 2,3-two chloro-5-bromo-4-aminomethyl phenyls
118? ? Br? CH 2 2,5-two bromo-3-chloro-4-aminomethyl phenyls
119? ? Br? CH 2 2-iodo-3-chloro-5-bromo-4-aminomethyl phenyl
120? ? Br? CH 2 2-fluoro-3-chloro-5-bromo-4-aminomethyl phenyl
121? ? Br? CH 2 3-chloro-5-bromo-4-p-methoxy-phenyl phenyl
122? ? Br? CH 2 2,3-two chloro-5-bromo-4-p-methoxy-phenyls
123? ? Br? CH 2 2,5-two bromo-3-chloro-4-p-methoxy-phenyls
124? ? Br? CH 2 2-iodo-3-chloro-5-bromo-4-p-methoxy-phenyl
125? ? Br? CH 2 2-fluoro-3-chloro-5-bromo-4-p-methoxy-phenyl
126? ? Br? CH 2 3-bromo-5-chloro-4-aminomethyl phenyl
127? ? Br? CH 2 2,5-two chloro-3-bromo-4-aminomethyl phenyls
128? ? Br? CH 2 2,3-two bromo-5-chloro-4-aminomethyl phenyls
129? ? Br? CH 2 2-iodo-3-bromo-5-chloro-4-aminomethyl phenyl
130? ? Br? CH 2 2-fluoro-3-bromo-5-chloro-4-aminomethyl phenyl
131? ? Br? CH 2 3-bromo-5-chloro-4-p-methoxy-phenyl
132? ? Br? CH 2 2,5-two chloro-3-bromo-4-p-methoxy-phenyls
133? ? Br? CH 2 2,3-two bromo-5-chloro-4-p-methoxy-phenyls
134? ? Br? CH 2 2-iodo-3-bromo-5-chloro-4-p-methoxy-phenyl
135? ? Br? CH 2 2-fluoro-3-bromo-5-chloro-4-p-methoxy-phenyl
136? ? Br? CH 2 3,5-dimethoxy-4 '-trifluoromethyl
137? ? Br? CH 2 2-chloro-3,5-dimethoxy-4 '-trifluoromethyl
138? ? Br? CH 2 2-bromo-3,5-dimethoxy-4 '-trifluoromethyl
139? ? Br? CH 2 2-iodo-3,5-dimethoxy-4 '-trifluoromethyl
140? ? Br? CH 2 2-fluoro-3,5-dimethoxy-4 '-trifluoromethyl
141? ? Br? CH 2 3,5-two bromo-4-Trifluoromethoxyphen-ls
142? ? Br? CH 2 2-chloro-3,5-two bromo-4-Trifluoromethoxyphen-ls
143? ? Br? CH 2 2,3,5-three bromo-4-Trifluoromethoxyphen-ls
144? ? Br? CH 2 2-iodo-3,5-two bromo-4-Trifluoromethoxyphen-ls
145? ? Br? CH 2 2-fluoro-3,5-two bromo-4-Trifluoromethoxyphen-ls
146? ? Br? CH 2 3,5-dimethyl-4-p-methoxy-phenyl
147? ? Br? CH 2 2-chloro-3,5-dimethyl-4-p-methoxy-phenyl
148? ? Br? CH 2 2-bromo-3,5-dimethyl-4-p-methoxy-phenyl
149? ? Br? CH 2 2-iodo-3,5-dimethyl-4-p-methoxy-phenyl
150? ? Br? CH 2 2-fluoro-3,5-dimethyl-4-p-methoxy-phenyl
151? ? Br? CH 2 3,5-dimethyl-4-bromophenyl
152? ? Br? CH 2 2-chloro-3,5-dimethyl-4-bromophenyl
153? ? Br? CH 2 2,4-two bromo-3,5-3,5-dimethylphenyl
154? ? Br? CH 2 2-iodo-3,5-dimethyl-4-bromophenyl
155? ? Br? CH 2 2-fluoro-3,5-dimethyl-4-bromophenyl
156? ? Br? CH 2 3,5-dimethyl-4-chloro-phenyl-
157? ? Br? CH 2 2,4-two chloro-3,5-3,5-dimethylphenyl
158? ? Br? CH 2 2-bromo-3,5-dimethyl-4-chloro-phenyl-
159? ? Br? CH 2 2-iodo-3,5-dimethyl-4-chloro-phenyl-
160? 1? Cl? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
161? 2? Cl? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
162? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
163? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
164? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
165? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
166? ? Cl? CH 2 3,5-dimethyl-4-bromopyridine-2-base
167? ? Cl? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
168? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-bromopyridine-2-base
169? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-bromopyridine-2-base
170? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
171? ? Cl? CH 2 4,6-two bromo-3,5-dimethyl-pyridine 1-oxide-2-base
172? ? Cl? CH 2 3,5-dimethyl-4-chloropyridine-2-base
173? ? Cl? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
174? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-chloropyridine-2-base
175? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-chloropyridine-2-base
176? ? Cl? CH 2 4,6-two chloro-3,5-dimethyl-pyridine 1-oxide-2-base
177? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
178? ? Cl? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
179? ? Cl? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
180? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-iodine pyridine-2-base
181? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-iodine pyridine-2-base
182? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
183? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
184? ? Cl? CH 2 3,5-dimethyl-4-thiomethyl pyridine-2-base
185? ? Cl? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
186? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl pyridine-2-base
187? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl pyridine-2-base
188? ? Cl? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
189? ? Cl? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
190? ? Cl? CH 2 3,4,5-trimethylammonium-pyridine-2-base
191? ? Cl? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
192? ? Cl? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine-2-base
193? ? Cl? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine-2-base
194? ? Cl? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
195? ? Cl? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
196? ? Cl? CH 2 4,5,6-trimethoxy pyridine-2-base
197? ? Cl? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
198? ? Cl? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
199? ? Cl? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
200? ? Cl? CH 2 3-chloro-4,5,6-trimethoxy-pyridine 1-oxide-2-base
201? ? Cl? CH 2 3-bromo-4,5,6-trimethoxy-pyridine 1-oxide-2-base
202? ? Cl? CH 2 3,4,5-trimethoxy pyridine-2-base
203? ? Cl? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
204? ? Cl? CH 2 3-bromo-3,4,5-trimethoxy pyridine-2-base
205? ? Cl? CH 2 3-chloro-3,4,5-trimethoxy pyridine-2-base
206? ? Cl? CH 2 3-chloro-3,4,5-trimethoxy-pyridine 1-oxide-2-base
207? ? Cl? CH 2 3-bromo-3,4,5-trimethoxy-pyridine 1-oxide-2-base
208? ? Cl? CH 2 4,5,6-trimethylammonium-pyridine-2-base
209? ? Cl? CH 2 4,5,6-trimethylammonium pyridine 1-oxide-2-base
210? ? Cl? CH 2 3-bromo-4,5,6-trimethylammonium-pyridine-2-base
211? ? Cl? CH 2 3-chloro-4,5,6-trimethylammonium-pyridine-2-base
212? ? Cl? CH 2 3-chloro-4,5,6-trimethylammonium pyridine 1-oxide-2-
? ? ? ? Base
213? ? Cl? CH 2 3-bromo-4,5,6-trimethylammonium pyridine 1-oxide-2-base
214? ? Cl? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
215? ? Cl? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
216? ? Cl? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine-2-base
217? ? Cl? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine-2-base
218? ? Cl? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
219? ? Cl? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
220? ? Cl? CH 2 4-bromo-5,6-dimethoxy-pyridine-2-base
221? ? Cl? CH 2 4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
222? ? Cl? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine-2-base
223? ? Cl? CH 2 3-chloro-4 bromo-5,6-dimethoxy-pyridine-2-base
224? ? Cl? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
225? ? Cl? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
226? ? Cl? CH 2 4,6-dimethyl-5-methoxyl group-pyridin-3-yl
227? ? Cl? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
228? ? Cl? CH 2 4,6-dimethyl-5-bromopyridine-3-base
229? ? Cl? CH 2 4,6-dimethyl-5-chloropyridine-3-base
230? ? Cl? CH 2 5,6-dimethyl-4-bromopyridine-3-base
231? ? Cl? CH 2 5,6-dimethyl-4-chloropyridine-3-base
232? ? Cl? CH 2 4,6-dimethyl-5-bromo-pyridine 1-oxide-3-base
233? ? Cl? CH 2 4,6-dimethyl-5-chloro-pyridine 1-oxide-3-base
234? ? Cl? CH 2 5,6-dimethyl-4-bromo-pyridine 1-oxide-3-base
235? ? Cl? CH 2 5,6-dimethyl-4-chloro-pyridine 1-oxide-3-base
236? ? Cl? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
237? ? Cl? CH 2 2,6-dimethyl-pyridin-4-yl
238? ? Cl? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
239? ? Cl? CH 2 2,3,6-trimethoxy-pyridin-4-yl
240? ? Cl? CH 2 2,6-dimethyl-3-bromopyridine-4-base
241? ? Cl? CH 2 2,6-dimethyl-3-chloropyridine-4-base
242? ? Cl? CH 2 2,6-two chloro-3-bromopyridine-4-bases
243? ? Cl? CH 2 2,6-two bromo-3-chloropyridine-4-bases
244? ? Cl? CH 2 2,3,6-three chloro-pyridin-4-yls
245? ? Cl? CH 2 2,3,6-three bromo-pyridin-4-yls
246? ? Cl? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
247? ? Cl? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
248? ? Cl? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
249? ? Cl? CH 2 2,3,6-trimethoxy-1-oxygen-pyridin-4-yl
250? ? Cl? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
251? ? Cl? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
252? ? Cl? CH 2 2,6-two chloro-3-bromo-1-oxygen-pyridin-4-yls
253? ? Cl? CH 2 2,6-two bromo-3-chloro-1-oxygen-pyridin-4-yls
254? ? Cl? CH 2 2,3,6-three chloro-1-oxygen-pyridin-4-yls
255? ? Cl? CH 2 2,3,6-three bromo-1-oxygen-pyridin-4-yls
256? ? Cl? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
257? ? Cl? CH 2 5,6-dimethyl-4-iodine pyridine-3-base
258? ? Cl? CH 2 4,5,6-trichloropyridine-3-base
259? ? Cl? CH 2 4,5,6-pyridinium tribromide-3-base
260? ? Br? CH 2 3,5-dimethyl-4-methoxypyridine-2-base
261? ? Br? CH 2 3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
262? ? Br? CH 2 6-bromo-3,5-dimethyl-4-methoxypyridine-2-base
263? ? Br? CH 2 6-chloro-3,5-dimethyl-4-methoxypyridine-2-base
264? ? Br? CH 2 6-chloro-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
265? ? Br? CH 2 6-bromo-3,5-dimethyl-4-methoxyl group-pyridine 1-oxide-2-base
266? ? Br? CH 2 3,5-dimethyl-4-bromopyridine-2-base
267? ? Br? CH 2 3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
268? ? Br? CH 2 6-bromo-3,5-dimethyl-4-bromopyridine-2-base
269? ? Br? CH 2 6-chloro-3,5-dimethyl-4-bromopyridine-2-base
270? ? Br? CH 2 6-chloro-3,5-dimethyl-4-bromo-pyridine 1-oxide-2-base
271? ? Br? CH 2 4,6-two bromo-3,5-dimethyl-pyridine 1-oxide-2-base
272? ? Br? CH 2 3,5-dimethyl-4-chloropyridine-2-base
273? ? Br? CH 2 3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
274? ? Br? CH 2 6-bromo-3,5-dimethyl-4-chloropyridine-2-base
275? ? Br? CH 2 6-chloro-3,5-dimethyl-4-chloropyridine-2-base
276? ? Br? CH 2 4,6-two chloro-3,5-dimethyl-pyridine 1-oxide
? ? ? ? -2-base
277? ? Br? CH 2 6-bromo-3,5-dimethyl-4-chloro-pyridine 1-oxide-2-base
278? ? Br? CH 2 3,5-dimethyl-4-iodine pyridine-2-base
279? ? Br? CH 2 3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
280? ? Br? CH 2 6-bromo-3,5-dimethyl-4-iodine pyridine-2-base
281? ? Br? CH 2 6-chloro-3,5-dimethyl-4-iodine pyridine-2-base
282? ? Br? CH 2 6-chloro-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
283? ? Br? CH 2 6-bromo-3,5-dimethyl-4-iodo-pyridine 1-oxide-2-base
284? ? Br? CH 2 3,5-dimethyl-4-thiomethyl pyridine-2-base
285? ? Br? CH 2 3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
286? ? Br? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl pyridine-2-base
287? ? Br? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl pyridine-2-base
288? ? Br? CH 2 6-chloro-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
289? ? Br? CH 2 6-bromo-3,5-dimethyl-4-thiomethyl-pyridine 1-oxide-2-base
290? ? Br? CH 2 3,4,5-trimethylammonium-pyridine-2-base
291? ? Br? CH 2 3,4,5-trimethylammonium-pyridine 1-oxide-2-base
292? ? Br? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine-2-base
293? ? Br? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine-2-base
294? ? Br? CH 2 6-chloro-3,4,5-trimethylammonium-pyridine 1-oxide-2-base
295? ? Br? CH 2 6-bromo-3,4,5-trimethylammonium-pyridine 1-oxide-2-
? ? ? ? Base
296? ? Br? CH 2 3,4,5-trimethoxy pyridine-2-base
297? ? Br? CH 2 3,4,5-trimethoxy-pyridine 1-oxide-2-base
298? ? Br? CH 2 6-bromo-3,4,5-trimethoxy-pyridine-2-base
299? ? Br? CH 2 6-chloro-3,4,5-trimethoxy-pyridine-2-base
300? ? Br? CH 2 6-chloro-3,4,5-trimethoxy-pyridine 1-oxide-2-base
301? ? Br? CH 2 6-bromo-3,4,5-trimethoxy-pyridine 1-oxide-2-base
302? ? Br? CH 2 4,5,6-trimethoxy pyridine-2-base
303? ? Br? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
304? ? Br? CH 2 3-bromo-4,5,6-trimethoxy pyridine-2-base
305? ? Br? CH 2 3-chloro-4,5,6-trimethoxy pyridine-2-base
306? ? Br? CH 2 3-chloro-4,5,6-trimethoxy-pyridine 1-oxide-2-base
307? ? Br? CH 2 3-bromo-4,5,6-trimethoxy-pyridine 1-oxide-2-base
308? ? Br? CH 2 4,5,6-trimethoxy pyridine-2-base
309? ? Br? CH 2 4,5,6-trimethoxy-pyridine 1-oxide-2-base
310? ? Br? CH 2 3-bromo-4,5,6-trimethylpyridine-2-base
311? ? Br? CH 2 3-chloro-4,5,6-trimethylpyridine-2-base
312? ? Br? CH 2 3-chloro-4,5,6-trimethylammonium-l-oxy picolinate-2-base
313? ? Br? CH 2 3-bromo-4,5,6-trimethylammonium-pyridine 1-oxide-2-base
314? ? Br? CH 2 4,6-dimethyl-5-methoxyl group-pyridine-2-base
315? ? Br? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
316? ? Br? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine
? ? ? ? -2-base
317? ? Br? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine-2-base
318? ? Br? CH 2 3-chloro-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
319? ? Br? CH 2 3-bromo-4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-2-base
320? ? Br? CH 2 4-bromo-5,6-dimethoxy-pyridine-2-base
321? ? Br? CH 2 4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
322? ? Br? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine-2-base
323? ? Br? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine-2-base
324? ? Br? CH 2 3-chloro-4-bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
325? ? Br? CH 2 3,4-two bromo-5,6-dimethoxy-pyridine 1-oxide-2-base
326? ? Br? CH 2 4,6-dimethyl-5-methoxyl group-pyridin-3-yl
327? ? Br? CH 2 4,6-dimethyl-5-methoxyl group-pyridine 1-oxide-3-base
328? ? Br? CH 2 4,6-dimethyl-5-bromopyridine-3-base
329? ? Br? CH 2 4,6-dimethyl-5-chloropyridine-3-base
330? ? Br? CH 2 5,6-dimethyl-4-bromopyridine-3-base
331? ? Br? CH 2 5,6-dimethyl-4-chloropyridine-3-base
332? ? Br? CH 2 4,6-dimethyl-5-bromo-pyridine 1-oxide-3-base
333? ? Br? CH 2 4,6-dimethyl-5-chloro-pyridine 1-oxide-3-base
334? ? Br? CH 2 5,6-dimethyl-4-bromo-pyridine 1-oxide-3-base
335? ? Br? CH 2 5,6-dimethyl-4-chloro-pyridine 1-oxide-3-base
336? ? Br? CH 2 2,6-dimethyl-3-Methoxy Pyridine-4-base
337? ? Br? CH 2 2,6-dimethyl-pyridin-4-yl
338? ? Br? CH 2 2,3,6-trimethylammonium-pyridin-4-yl
339? ? Br? CH 2 2,3,6-trimethoxy-pyridin-4-yl
340? ? Br? CH 2 2,6-dimethyl-3-bromopyridine-4-base
341? ? Br? CH 2 2,6-dimethyl-3-chloropyridine-4-base
342? ? Br? CH 2 2,6-two chloro-3-bromopyridine-4-bases
343? ? Br? CH 2 2,6-two bromo-3-chloropyridine-4-bases
344? ? Br? CH 2 2,3,6-three chloro-pyridin-4-yls
345? ? Br? CH 2 2,3,6-three bromo-pyridin-4-yls
346? ? Br? CH 2 2,6-dimethyl-3-methoxyl group-1-oxygen-pyridin-4-yl
347? ? Br? CH 2 2,6-dimethyl-1-oxygen-pyridin-4-yl
348? ? Br? CH 2 2,3,6-trimethylammonium-1-oxygen-pyridin-4-yl
349? ? Br? CH 2 2,3,6-trimethoxy-1-oxygen-pyridin-4-yl
350? ? Br? CH 2 2,6-dimethyl-3-bromo-1-oxygen-pyridine-4-base
351? ? Br? CH 2 2,6-dimethyl-3-chloro-1-oxygen-pyridine-4-base
352? ? Br? CH 2 2,6-two chloro-3-bromo-1-oxygen-pyridin-4-yls
353? ? Br? CH 2 2,6-two bromo-3-chloro-1-oxygen-pyridin-4-yls
354? ? Br? CH 2 2,3,6-three chloro-1-oxygen-pyridin-4-yls
355? ? Br? CH 2 2,3,6-three bromo-1-oxygen-pyridin-4-yls
356? ? Br? CH 2 4,6-dimethyl-5-iodine pyridine-3-base
357? ? Br? CH 2 5,6-dimethyl-4-iodine pyridine-3-base
358? ? Br? CH 2 4,5,6-trichloropyridine-3-base
359? ? Br? CH 2 4,5,6-pyridinium tribromide-3-base
360? ? Cl? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
361? ? Br? CH 2 4,5,6-trimethoxy-3-chloropyridine-2-base
362? ? Cl? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
363? ? Br? CH 2 4,5,6-trimethoxy-3-bromopyridine-2-base
364? ? Cl? CH 2 4,5,6-trimethoxy-pyridin-3-yl
365? ? Cl? CH 2 4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
366? ? Cl? CH 2 2-bromo-4,5,6-trimethoxy-pyridin-3-yl
367? ? Cl? CH 2 2-chloro-4,5,6-trimethoxy-pyridin-3-yl
368? ? Cl? CH 2 2-chloro-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
369? ? Cl? CH 2 2-bromo-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
370? ? Cl? CH 2 4,5,6-trimethylammonium-pyridin-3-yl
371? ? Cl? CH 2 4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl
372? ? Cl? CH 2 2-bromo-4,5,6-trimethylammonium-pyridin-3-yl
373? ? Cl? CH 2 2-chloro-4,5,6-trimethylammonium-pyridin-3-yl
374? ? Cl? CH 2 2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
375? ? Cl? CH 2 2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
376? ? Cl? CH 2 2-iodo-4,5,6-trimethylammonium-pyridin-3-yl
377? ? Cl? CH 2 2-iodo-4,5,6-trimethylammonium-pyridin-3-yl
378? ? Br? CH 2 4,5,6-trimethoxy-pyridin-3-yl
379? ? Br? CH 2 4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
380? ? Br? CH 2 2-bromo-4,5,6-trimethoxy-pyridin-3-yl
381? ? Br? CH 2 2-chloro-4,5,6-trimethoxy-pyridin-3-yl
382? ? Br? CH 2 2-chloro-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
383? ? Br? CH 2 2-bromo-4,5,6-trimethoxy-1-oxygen-pyridin-3-yl
384? ? Br? CH 2 4,5,6-trimethylammonium-pyridin-3-yl
385? ? Br? CH 2 4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl
386? ? Br? CH 2 2-bromo-4,5,6-trimethylammonium-pyridin-3-yl
387? ? Br? CH 2 2-chloro-4,5,6-trimethylammonium-pyridin-3-yl
388? ? Br? CH 2 2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
389? ? Br? CH 2 2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridine-3-base
Compound useful in the table 4 is: 2,3,13,82,83,162,163,168,169,174,175,180,181,186,187,192,193,198,199,204,205,210,211,228,229,230,231,232,233,234,235,236,237,250,251,262,263,268,269,274,275,280,281,286,287,292,293,298,299,304,305,310,311,316,317,328,329,338,372,373,380 and 381 (from what wherein select is 162,163,168,169,174,175,180,181,186,187,192,193,198,199,204,205,228,229,262,263,268,269,274,275,280,281,286,287,292,293,316,317,328 and 329).
III. The compounds of this invention is synthetic
The synthetic of The compounds of this invention can be realized by the whole bag of tricks known in the art, is included in for example Montgomery, J.Med.Pharm.Chem., 1962,5,15-24; Sircar, U.S. patent 4,772,606,1988; Sircar, U.S. patent 4,748,177,1988; Hans, U.S. patent 5,110,818,1992; Gillespie, the open No.WO 02/055521 of PCT; Matsuda, JP10025294A2,1998; Hans, those methods of describing among the open No.US2003/0078413 of U.S. patent 5,110,818,1992 and U.S..It has illustrated the synthetic of the some embodiments of the present invention.Described method also can be used for other group.
A. Synthesizing of formula I compound and related analogs
Formula I compound of the present invention and related analogs can be synthetic by the whole bag of tricks known in the art.In order to illustrate, in scheme 1, summarized the route of synthetic pyrrolopyrimidine, it comprises three steps: (1) makes up bicyclic system with the precursor of pyridine, pyrimidine, pyrroles or acyclic; (2) connect described R 5-R 4Described ring system is further modified in-group and (3).
Importantly, this area the art personnel can recognize, the order of construction effect might not be (1)-(2)-(3), and these construction effect can exchange mutually, can be compatible between the functional group that is used for certain point as long as specify under reagent and this situation.
Scheme 1
And as shown in Figure 1, the starting material of formula 1,4,5 and I or intermediate can exist with the form of tautomer, and do not use two kinds of forms in this patent with making any distinction between.
Figure GSA00000083249102021
Fig. 1
Fig. 1
1. Synthesizing of pyrrolo-[2,3-d] pyrimidine
1.1 with the pyrimidine is synthetic pyrrolo-[2, the 3-d] pyrimidine of raw material
As summarizing in the scheme 2, can be by pyrimidine preparation formula 4 compounds.For example: with the pyrimidine is raw material
The method of the 5-unit ring of preparation compound (4)
Figure GSA00000083249102031
Scheme 2
Scheme 2
Method 1.1.1
As shown in the formula 6, formula 4 compounds can prepare by the intramolecular cyclization of aldehydes or ketones (can be protected).(referring to, J.Davoll, J.Chem.Soc.1960,131; J.A.Montgomery, J.Chem.Soc.1967,665; G.Cristalli, J.Med.Chem.1988,31,390; T.Miwa, J.Org.Chem.1993,58,1696; D.M.Williams., J.Chem.Soc., Perkin Trans 1,1997,1171).
Method 1.1.2
With ammonia treatment R is that formula 7 compounds of halogen or leavings group can prepare R 3Be H, R 6Be Cl and R 7Be NH 2Formula 4 compounds.Equally, at alkali K for example 2CO 3, Cs 2CO 3, i-PrNEt 2Exist down, in butanols, under reflux state, use R 5-R 4-NH 2Processing R is that formula 7 compounds of halogen or leavings group can prepare R 3Be H, R 1Be Cl and R 2Be NH 2Formula I compound.(A.B.Reitz?J.Med.Chem.1994，37，3561)。And formula 7 compounds can be according to G.W.Craig J.Prakt.Chem.2000, and the instruction in 342,504 and M Semonsky Coll.Czech.Chem.Commun.1980,45,3583 prepares.
Method 1.1.3
The α-Lu Daitong that is the formula 8 of halogen with ammonia or its synthetic Equivalent processing X can obtain formula 4 compounds.
Method 1.1.4
Can obtain R by the intramolecular cyclization/double-bond migration that formula 9 alkene is carried out successively the Pd-media 0Formula 4 compounds for methyl.(S.E.Watson，Synth.Commun.1998，28，3885)。
Method 1.1.5
The intramolecular cyclization of the Pd-media of through type 10 alkene can obtain R 3Be formula 4 compounds of H, wherein Z is as electron-withdrawing group, for example tosyl group or EtCOO 2-.
Method 1.1.6
R 3For the intramolecularly of precursor that formula 4 compounds of AcO-can through type 11 pay-the Ke acylation reaction makes (E.D.Edstrom, J.Org.Chem.1993,58,403).
Method 1.1.7
Use formula R 3The alpha-halogen aldehyde of-CHX-CHO is handled formula 12 compounds can make R 0Be H, R 6Be OH and R 7Be NH 2Formula 4 compounds.Referring to, D.M.Williams, J.Chem.Soc., Perkin Trans 1,1997,1171; C.J.Barnett, Org.Proc.Res.Devop.1999,3,184; A.Gangiee, J.Med.Chem.2001,44,1993.
Method 1.1.8
Use formula R 3The aldehyde of-CHO is handled formula 13 compounds can obtain R 6Be OH and R 7Be NH 2Formula 4 compounds.Referring to, A.Gangjee, J.Med.Chem.2003,46,591; E.C.Taylor, Heterocycles 1996,43, and 323.
1.2 with pyrroles is synthetic pyrrolo-[2, the 3-d] pyrimidine of raw material
Formula 4 compounds can also be made by the pyrroles of formula 2.Have the various methods that can form 6-unit ring (for example, R.J.Bontems, J.Med.Chem, 1990,33,2174 and reference wherein).For example,
Scheme 3
Scheme 3
Can be with R 13For-CN and R 14Be R-NH-CR 7The formula 2 compound cyclisation of=N-and rearrangement are to obtain R 6Formula 4 compounds for R-NH-.Referring to, E.C.Taylor, J.Am.Chem.Soc.1965,87,1995.
Can use thiocarbamide, guanidine or chloromethane amidine to handle R 13For-CN and R 14For-NH 2Formula 2 compounds to obtain R 6For-NH 2And R 7For-NH 2Formula 4 compounds.Referring to, H.Kosaku, Heterocycles, 2001,55,2279; A.Gangjee, US patent 5,939,420 (1999).
Can handle R with the acetate carbonamidine 13For-CN and R 14For-NH 2Formula 2 compounds to obtain R 6For-NH 2And R 7Formula 4 compounds (J.A.Montgomery, J.Chem.Soc.1967,665) for H.With DMF-DMA or such as (EtO) 3The ortho ester of CH is handled, and handles with amine more afterwards and can finish same conversion.Referring to, E.C.Taylor, J.Am.Chem.Soc, 1965,87,1995.
Can handle R with formic acid 13For-CN and R 14For-NH 2Formula 2 compounds to obtain R 6For-OH and R 7Formula 4 compounds (K.A.M.El-Bayouki, J.Chem.Res.Miniprint, 1995,1901) for H.
Can under the Vilsmeyer-Haack condition, (MDF/POCl3) handle R 13For-CO 2NH 2And R 14For-NH 2Formula 2 compounds to obtain R 6For-OH or Cl and R 7Formula 4 compounds for H.Referring to, K.A.M.El-Bayouki, J.Chem.Res.Miniprint, 1995,1901.
Can use CS 2Or EtOCS 2K handles R 13For-CONH 2And R 14For-NH 2Formula 2 compounds to obtain R 6For-OH and R 7Formula 4 compounds for-SH.Referring to, S.M.Bennett, J.Med.Chem.1990,33,2162.
1.3 with the acyclic precursor is synthetic pyrrolo-[2, the 3-d] pyrimidine of raw material
Formula 14 compounds can be according to situation about summarizing in the scheme 4 by acyclic precursor preparation (T.Miwa, J.Med.Chem.1991,34,555).
Figure GSA00000083249102061
Scheme 4
2. -R 4 -R 5 Pulsating combination
2.1 the alkylation of formula 4 compounds
At alkali K for example 2CO 3, NaH, Cs 2CO 3, DBU etc. existence under, exist/do not have catalyzer for example NaI, KI, (Bu) 3Under the condition of NI etc., for example among DMF, THF, the DMSO etc., use for example L of electrophilic reagent at polar solvent 1-R 4-R 5(L wherein 1Be leavings group) can carry out alkylation to formula 4 compounds.Referring to scheme 5.Leavings group includes but not limited to that for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate, triphenyl phosphorus (generate, for example PPh under the Mitsunobu condition 3/ DEAD) etc.Referring to Kasibhatla, PCT publication number WO 03/037860.
Figure GSA00000083249102062
Scheme 5
2.2. electrophilic reagent L 1-R 4-R 5Preparation, L wherein 1Be leavings group
2.2.1. the benzylic type electrophilic reagent is synthetic
Figure GSA00000083249102063
Fig. 2
Fig. 2
Can use the whole bag of tricks of reporting in the document, prepare electrophilic reagent by the benzene derivative that replaces, referring to Jerry March, Advanced Organic Chemistry, 4 ThVersion; Larock, Comprehensive Organic Transformations, 1989, VCH, New York.For example, L 1For the compound of Br can carry out halogenation and prepare afterwards by corresponding phenylformic acid of reduction or phenyl aldehyde again.These benzyl derivatives can also be prepared by the oxidation of benzyl or the halogenation of benzyl.Other modification of benzyl rings can be carried out before or after the alkylation step of pyrrolo-[2,3-d] pyrimidine.
2.2.2. picolyl type electrophilic reagent is synthetic
Figure GSA00000083249102071
Fig. 3
Fig. 3
These compounds can be by many method preparations of reporting in the document.
Morisawa, J.Med.Chem.1974,17,1083; Klaus, W., J.Med.Chem.1992,35,438; Abramovitch, R.A.; Smith, E.M., " the Pyridine-1-oxide in Pyridine and itsDerivatives, " among the The Chemistry ofHeterocyclic Compounds; Weissberger, A., Taylor, E.C., Eds.; John Wiley, New York, 1974, Pt.2, pp1-261; Jeromin, G.E., Chem.Ber.1987,120,649.Blanz, E.J., J.Med.Chem.1970,13,1124; Smith, Kline and French, EP applies for EP0184322,1986; Abblard, J., Bull.Soc.Chim.Fr.1972,2466; Fisher, B.E., TheStructure of Isomaltol.J.Org.Chem.1964,29,776.De?Cat，A.，Bull.Soc.Chim.Belg.1965，74，270；Looker，J.H.，J.Org?Chem.1979，44，3407。Ackerman, J.F.Ph.D.Dissertation, University of Notre Dame, Australia, June, 1949.These methods can be used for the synthetic of quinoline and isoquinoline 99.9 type compound.
2.3. by nucleophilic substitution combination-R 4-R 5Segment.
Under the certain situation ,-R 4-R 5Group can also connect before [2,3-d] pyrimidine dicyclo at the structure bicyclic pyrrole, and this has carried out more detailed description (the 4th section, scheme 8 and 9) below.In these cases, can use NH 2-R 4-R 5Connect-R by fragrant nucleophilic substitution 4-R 5Group.Under 20-160 ℃, in autoclave, handle L with amine 1-R 4-R 5Obtain compound N H 2-R 4-R 5L 1For-NH 2Corresponding amine can pass through prepared in various methods, for example use amine by L 1Be leavings group, as the compound of chlorine, bromine, tosylate, methanesulfonate etc., perhaps with hydrogenation preparation again after the sodiumazide.
3. The further modification of ring system
3.1.R 0Functional group change mutually
The three bromo pyrimi piperidine oxidation R that in the trimethyl carbinol/vinegar stock, support with three bromo pyrimi piperidines or polymkeric substance 0Be the formula IA compound of H, it can be oxidized to the formula I compound of R0 with zinc reduction more afterwards for-OH.Referring to, C.Liang, US patent 6,610,688 (2000); L.Sun, Bioorg Med.Chem Lett., 2002,12,2153.
Can handle R down in Mannich condition (HCHO+HNRR ') 0For the formula I compound of H to obtain R 0Formula IA compound for-CH-NRR '.Referring to F.Seela, Synthesis, 1997,1067.
R 0For the formula IA compound of H can carry out lithiumation and with electrophilic reagent (for example, I 2, ArCHO) handle, to generate R 0For for example-I or-the formula IA compound of CH (OH) Ar.Referring to, E.Bisagni, Tetrahedron, 1983,39,1777; T, Sakamoto, TetrahedronLett.1994,35,2919; T.Sakamoto, J.Chem.Soc., Perkin Trans 1,1996,459.
3.2.R 1Functional group change mutually
Can adopt standard conditions POCl 3, POBr 3Deng, there is being/do not having for example Et of alkali 3N, N, accelerine, (i-Pr) 2NEt etc. and have/do not have for example BnEt of catalyzer 3N +Cl -Under the condition that exists, at polar solvent CH for example 3CN, CH 2Cl 2Deng in R 1For the formula IA compound of OH is converted into halogenide.Methods involving includes but not limited to SOCl 2/ DMF (M.J.Robins, Can.J.Chem.1973,12,3161), PPh 3/ CC 14(L.De Napoli, J.Chem.Soc.Perkin Trans 1,1994,923), HMPT/CC 14Or HMPT/NBS (E.A.Veliz, Tetrahedron Lett, 2000,41,1695) or PPh 3/ I 2(X.Lin, Org.Letters, 2000,2,3497).
Can pass through Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO 2/ H +, NOBF 4, RONO) and halogenic donator (BF 4 -, CuX 2, SbX 3, wherein X is a halogen) and with R 1For-NH 2Formula IA compound be converted into halogenide.
R 1For the formula IA compound of alkyl can be by R 1Formula 4 compound (A.Holy, J.Med.Chem.1999,42,2064) for halogen and trialkylaluminium or dialkyl group zinc.
Can use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +) with R 1For halid formula IA compound is converted into R 1For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound (for example, B.G.Ugarkar, J.Med.Chem.2000,43,2883-2893 and 2894-2905).
Can use ammonia treatment R 1Be the formula IA compound of halogen or another leavings group, to generate R 1For-NH 2Formula IA compound (F.Seela, Liebigs.Ann.Chem.1985,315).
3.3.R 2Functional group change mutually
Can be with R 2For-NH 2The temporary protection of formula IA compound get up, for example become acid amides (Ac 2O, PivCl), carbamate (tBoc) 2O) or amidine (DMF-DMA).
Can pass through Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO 2/ H +, NOBF 4, RONO) and halogenic donator (BF 4 -, CuX 2, SbX 3) with R 2For-NH 2Formula IA compound be converted into halogenide.
Can use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +) with R 2For halid formula IA compound is converted into R 2For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound.
R 2For the formula IA compound of-SH can be converted into halogenide (Br 2).It can also oxidized (for example, H 2O 2) and with ammonia treatment to obtain-NH 2Group (S.M.Bennett, J.Med.Chem.1990,33,2162).
R 2Be sulfide, for example the formula IA compound of MeS-can be converted into sulfone, for example MeSO 2 -, and by nucleophilic reagent, NH for example 3Or NH 2-NH 2, N 3-, CN-replaces.
3.4.R 3Functional group change mutually
Can be to R 3For the formula IA compound of H carries out halogenation (J.F.Gerste, J.Chem.Soc.1969,207), and by the catalytic reaction of Pd-((a) Sonogashira coupling: E.C.Taylor etc., Tetrahedron, 1992,48,8089; (b) carboxylation: J.W.Pawlik, J.Heterocycl.Chem.1992,29,1357; Suzuki coupling: T.Y.I Wu, Org.Lett., 2003,5,3587) or the addition by nucleophilic reagent and further functionalized (for example, hydrazine, B.M.Lynch, Can.J.Chem.1988,66,420) (c).
Can be to R 3For the formula IA compound of-CHO carries out the Bayer-Villiger oxidation, to generate R 3Formula IA compound for-O-CHO.The latter can be hydrolyzed into R 3For-OH.(A.S.Bourlot，E.Desarbre，J.Y.Mérour?Synthesis?1994，411)。
Can handle R down in Mannich condition (HCHO+HNRR ') 3For the formula IA compound of H to obtain R 3Formula IA compound (F.Seela, Synthesis, 1997,1067) for-CH-NRR '.
Can obtain R by the Mannich reaction 3For-CH 2-NBn 2Formula IA compound, use formula NH 2The aniline of-Ar is further handled to obtain R 3For-CH 2The formula IA compound of-NH-Ar (D.C.Miller, J.Med.Chem.2002,45,90).
Can be with BuLi to R 3Replace for the formula IA compound of Br carries out metal, and with electrophilic reagent for example MeI handle, to obtain R 3Formula IA compound for methyl.R 1For-Cl and R 3For the formula IA compound of-Br can be at R 3On carry out selective metal and replace (J.S.Pudlo, J.Med.Chem.1990,33,1984).
Can be to R 0For-OH and R 3For the formula IA compound of H carries out monoalkylation or two-alkylation, to obtain R 1Formula ID compound for alkyl.Can exist/not exist such as NaI, KI, (Bu) in the presence of such as the alkali of KHMDS, LHMDS, LDA etc. 3Under the condition of the catalyzer of NI etc., for example among THF, the DMSO etc., use electrophilic reagent, for example L at polar solvent 1-R 3(L wherein 1Be leavings group) the realization alkylation.Leavings group includes but not limited to, for example halogen, trifluoromethanesulfonic acid root, tosylate or methanesulfonate.
Figure GSA00000083249102101
Scheme 6
For example in the acetonitrile/water, for example ruthenium tetroxide can be with R with oxygenant at binary solvent 0Be H and R 3For the formula IA compound oxidation of H is the compound of formula 16/IE.(G.W.Gribble?Org.Prep.Proced.Int.2001，33(6)，615)。
In the presence of cobalt (III) catalyzer, use oxygenant, for example tin anhydride or oxygen can be with R 0For-OH and R 3For the formula IA compound oxidation of H is R 3Formula IC compound for oxo.(SeO 2Oxidation: Romeo Helv.Chin.Acta.1955,38,463,465.The oxygen oxidation: A.Inada Heterocycles 1982,19,2139).
3.5.R 5Further modification
R 5Especially can be as required when it is aryl or heteroaryl for example palladium coupling by halogenation, nitrated, halogen, pay-reactions such as Ke alkylation/acylations are by further modification; perhaps these modification can also be carried out before alkylation; referring to Jerry March, AdvancedOrganic Chemistry.Can also use for example H of various oxygenants 2O 2, O 3, MCPBA etc., at polar solvent CH for example 2Cl 2, CHC 13, CF 3Among the COOH etc. hetero-aromatic ring is oxidized to its corresponding N-oxide compound.Referring to Jerry March, Advanced Organic Chemistry, 4 ThVersion, 19 chapters.The example of various modification is pointed out in scheme 7.
Scheme 7
4. The variation of Build Order
As mentioned above, make up synthetic (2) R of reaction (1) bicyclic system 5-R 4The connection of-part and the further modification of (3) ring system are not to carry out with the order of (1)-(2)-(3), and it can advantageously carry out with different order.
Method 4.1.
Scheme 8 has shown that the structure reaction sequence is not the synthetic method of (2)-(1)-(3) for (1)-(2)-(3).At first the nucleophilic substitution by aromatic ring connects upward R 5, make up bicyclic system then, modify at last.
Figure GSA00000083249102121
Scheme 8
Method 4.1.1
At alkali K for example 2CO 3, Cs 2CO 3Or iPrNEt 2Exist down, in butanols, under refluxing, use R 5-R 4-NH 2Processing formula 17 compounds can prepare R 1Be Cl and R 2Be NH 2Formula 18 compounds.(A.B.Reitz?J.Med.Chem.1994，37，3561)。
Method 4.1.2
In the presence of halogenating agent and the acid such as acetic acid or tosic acid such as bromine, N-bromo-succinimide, iodine or N-iodine succimide, the compound by return-flow type 18 in chloroform or ethylene dichloride can prepare R 1Be Cl and R 2Be NH 2Formula 19 compounds.(A.P.PhillipsJ.Am.Chem.Soc.1952，74，3922)。
Method 4.1.3
Coupling type 19 compounds and trimethyl silyl acetylene under the Sonogashira condition use dichloro hexyl borine to carry out hydroboration afterwards and use hydrogen peroxide to carry out oxidation in the presence of sodium hydroxide, can prepare R 1Be Cl and R 2Be NH 2Formula 20 compounds.(Sonogashira coupling: E.C.Taylor Tetrahedron, 1992,48,8089.Hydroboration/oxidation: G.Zweifel J.Am.Chem.Soc.1976,98,3184).
Method 4.1.4
At oxalyl chloride, thionyl chloride, methylsulfonyl chloride or carbonochloridic acid alkyl ester, alkali iPrNEt for example 2Or pyridine exists down, at polar aprotic solvent, for example in THF, DME or the dioxane heating-type 20 compounds can, can prepare R 1Be Cl and R 2Be NH 2Formula 21 compounds.Use coupling reagent, for example DCC/HOBt, DCC/DMAP or EDCI/HOBt processing formula 20 compounds also can prepare it.(R.C.Larock Comprehensive OrganicTransformations second edition, 1870 pages).
Method 4.2
Equally, as mentioned above, make up synthetic (2) R of reaction (1) bicyclic system 5-R 4The connection of-part and the further modification of (3) ring system are not to carry out with the order of (1)-(2)-(3), and it can advantageously carry out with different order.For illustrative purposes, scheme 9 has shown the building-up process of supposition, and wherein Build Order is not (1)-(2)-(3) but (2)-(1)-(3).At first the nucleophilic substitution by aromatic ring connects R 5, make up bicyclic system then, at last it is modified.
Figure GSA00000083249102131
Scheme 9
Method 4.3
For illustrative purposes, scheme 10 has shown the building-up process of supposition, and wherein Build Order is not (1)-(2)-(3) but (1)-(3)-(2)-(3).At first make up dicyclo, then it is modified, connect R afterwards 4-R 5Part is further modified bicyclic system (deprotection) at last again.
Figure GSA00000083249102132
Scheme 10
Equally, if R for example 5Be pyridine, then can before or after alkylation, be translated into the N-oxide compound.
B. Synthesizing of formula II compound (imidazopyridine and aminopurine) and related analogs
Formula II compound can synthesize by known the whole bag of tricks in the affiliated field.Summarized synthesizing amino purine (formula IIC﹠amp in the scheme 11; IID) general strategy.Other member of formula II compound also can be synthetic according to this path.Should be appreciated that, can also use other method.
Figure GSA00000083249102141
Scheme 11
As shown in Figure 4, formula 2 or/and 4 raw material or intermediate can exist with the form of tautomer.Material to two kinds of forms is described as broad as longly in this manual.
Fig. 4
1. Method 1: prepare by purine:
Formula IIC compound (referring to, scheme 12) can be synthetic by commercially available raw material heterocycle, for example R 6For-Cl ,-Br or-OH, R 7For-NH 2And R 8For formula 2 compounds of-H commercially available from Aldrich, AlfaAesar etc.Therefore, can be such as K 2CO 3, NaH, Cs 2CO 3, DBU etc. alkali exist down, have/do not have halogenide for example NaI, KI, (Bu) 3Under the condition that NI etc. exist,, for example among DMF, THF, the DMSO etc., use electrophilic reagent, for example L at polar solvent 1-R 4-R 5(wherein-L 1Be leavings group) formula 2 is carried out alkylation.Leavings group includes but not limited to for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate
Figure GSA00000083249102151
Scheme 12
Deng.Referring to Kasibhatla, PCT publication number WO 03/037860.Can adopt standard conditions POC 13, POBr 3Deng, having/do not have such as Et 3N, N, N-Diethyl Aniline, (i-Pr) 2Under the condition that the alkali of NEt etc. exists, at polar solvent CH for example 3CN, CH 2C 12Deng in, with R 1For the formula I compound of OH is converted into halogenide.
At alkali K for example 2CO 3Or NaH and polar solvent for example there are down R in DMF or THF 1Formula IIC compound and HOR for halogen 11, HSR 11Or NH 2R 8Reaction can preparation formula IIC compound, wherein R 1For-OR 11,-SR 11Or-NHR 8(R wherein 11Be alkyl), R 8For hydrogen, low alkyl group, lower aryl or-C (O) R 9, R wherein 9For low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11(R wherein 10Independent is hydrogen or low alkyl group).Work as R 1During for hydroxyl, can prepare R by simple acylation reaction 8For-C (O) R 9Formula IIC compound.
R 1For the formula IIC compound of alkyl can be by R 1Formula II compound for halogen and trialkylaluminium or dialkyl group zinc.(referring to Holy, J.Med.Chem.1999,42,2064).
R 5Especially can be as required when it is aryl or heteroaryl for example palladium coupling by halogenation, nitrated, halogen, pay-reactions such as Ke alkylation/acylations are by further modification; perhaps these modification can also be carried out before alkylation; referring to Jerry March, AdvancedOrganic Chemistry.Use for example H of various oxygenants 2O 2, O 3, MCPBA etc., at polar solvent CH for example 2C 12, CHC 13, CF 3Hetero-aromatic ring can also be oxidized to its corresponding N-oxide compound among the COOH etc.Referring to Jerry March, Advanced Organic Chemistry, 4 ThVersion, 19 chapters.
Can for example in DMF, water or the suitable buffered soln, use for example Br of halogenating agent at polar solvent 2, NBS, NCS, NIS etc., by formula 1 or 2 preparation R 3Formula IIC compound for halogen.Referring to Herdewijn, J.Med.Chem.1995,38,3838.Alternatively, R 8Known step makes in the document for formula 2 compounds of iodine can also use, Burger for example, J.Org.Chem.2000,65,7825.These materials can be as required by further modification; For example, at polar solvent for example among DMF, the DMSO etc., by with trinitride NaN for example 3, LiN 3Perhaps for example reaction such as KCN or NaCN of prussiate obtains R3 and is-N 3Or-compound of CN.Referring to Halbfinger, J.Med.Chem.1999,42,1625; Jacobson, J.Med.Chem.1999,42,5325.
2. Method 2: prepare by pyrimidine
Formula IIC compound can also be by the substituted pyrimidines preparation (referring to scheme 13) of formula 5.Therefore, at organic bases Et for example 3N, (i-pr) 2NEt etc. exist down, at solvent for example among EtOH, the BuOH etc., and commercially available, R 16For hydrogen or-NO 2Formula 5 compounds (referring to J.Chem.Soc.1962,4186, be used to prepare R 16=-NO 2Compound) and NH 2-R 4-R 5Reaction is used nitrous acid to carry out nitrosification afterwards and (is worked as R 16=-H) used formula 6 (R then 16=-NO or-NO 2) V-Brite B or reduction such as Zn/HCOOH, thereby obtain
Scheme 13
R 16Be NH 2Formula 6 compounds.According to J.Chem.Soc.1963,4186; Sircar, U.S. patent 4,748,177,1988; And Dang, standard conditions are adopted in the description among the WO 98/39344, for example triethyl orthoformate, formic acid, cyanogen bromide etc., condensation R 16For-NH 2Formula 6 compounds, afterwards and POC 13Reaction obtains scheme 13, the compound of formula II.These compounds of formula IIC can further as required modification.
Similarly, formula IIC compound can also be by the 2-amino-4 of formula 7, and 6-dichloro pyrimidine synthetic (referring to scheme 14) is synthetic.At organic bases Et for example 3N, (ipr) 2Net etc. exist down, at solvent for example among EtOH, the BuOH etc., and formula 7 compounds and NH 2-R 4-R 5Reaction is afterwards in HCl solution and by 4-chloroaniline and NaNO 2
Figure GSA00000083249102171
Scheme 14
The diazonium salt reaction that makes obtains R 16Formula 8 compounds for azo-group-(4-chlorobenzene).In acetic acid, obtain R with zinc reducing couple nitrogen compound 16Be NH 2Formula 8 compounds.(referring to, Meier, U.S. patent 5,204,353 (1993)).According to J.Chem.Soc.1963,4186; Sircar, U.S. patent 4,748,177,1988; And Dang, standard conditions are adopted in the description among the WO 98/39344, for example triethyl orthoformate, formic acid, cyanogen bromide etc., and these compounds of condensation, afterwards and POCl 3Reaction obtains scheme 14, the compound of formula IIC.These compounds of formula IIC can further as required modification.
Equally, can also be as Daluge, U.S. patent 5,917, the description in 042 (1999), by commercially available 2,5-diamino-4, the 6-dihydroxy-pyrimidine makes R 16Be NH 2Formula 8 compounds, referring to scheme 15.
Figure GSA00000083249102172
Scheme 15
3. Method 3: prepare by imidazoles
As shown in scheme 6, formula IIC compound can also be by the imidazoles preparation that replaces.Therefore, can be at alkali for example KOH, NaOH, K 2CO 3, NaH, Cs 2CO 3, DBU etc. exists down, having/do not having halogenide for example NaI, KI, (Bu) 3Under the condition that NI etc. exist, for example among DMF, THF, the DMSO etc., use for example L of electrophilic reagent at polar solvent 1-R 4-R 5(wherein-L 1Be leavings group) to R 14Be NH 2, R 13Be C (O) NH 2And R 15For formula 4 compounds of H carry out alkylation.In order to obtain formula 10 compounds, leavings group includes but not limited to for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate etc.Use document Alhede, J.Org.Chem., 1991,2139 and the reference wherein quoted in many methods of reporting can realize ring closure, thereby obtain R 1Guanine for the formula II of OH.As discussed previously, use POC 13These compounds can be converted into R 1Formula II compound for Cl.Advantageously, as shown in scheme 16, these steps can be via formula 11 reverse carrying out.Alternatively, can also be as Chowdhury, J.Med.Chem.1999, the description in 42,4300, by reacting with the guanidinesalt hydrochlorate, and by R 14For-OH or halogenide, R 13For-C (O) OEt and R 15Formula 4 compounds for-H make up these 2-aminopyrimidine rings.
Figure GSA00000083249102181
Scheme 16
Wherein-L 1 Electrophilic reagent L for leavings group 1 -R 4 -R 5 And nucleophilic reagent NH 2 -R 4 -R 5 Preparation.
Synthesizing of benzylic type electrophilic reagent:
Can described in top III.A.2.2.1, use the prepared in various methods benzylic type electrophilic reagent of reporting in the document (Fig. 2 the preceding), referring to Jerry March, Advanced OrganicChemistry, 4 ThVersion; Larock, Comprehensive Organic Transformations, 1989, VCH, New York.For example, L 1For the compound of Br can prepare by the reduction of phenylformic acid or aldehyde derivatives and halogenation subsequently.These benzyl derivatives can also prepare by the oxidation of benzyl or the halogenation of benzyl.The further modification of benzyl rings can be carried out L before or after corresponding amine 1For-NH 2Amine can use ammonia by L 1Be leavings group, for example the compound of chlorine, bromine, tosylate, methanesulfonate etc.
Synthesizing of pyridylmethyl type electrophilic reagent:
Can prepare pyridylmethyl type electrophilic reagent by many methods of reporting in the document, it comprises those documents that provide among the III.A.2.2.2.
The further modification of pyridine ring can be carried out after the purine alkylation, referring to scheme 16.
Figure GSA00000083249102191
D. Synthesizing of formula III compound (pyrazolopyrimidine and related analogs)
Compound of the present invention can synthesize by known the whole bag of tricks in the affiliated field, comprises for example Gillespie, the open No.WO 02/055082 of PCT; Dempcy, those methods of describing among the open No.US2003/0078413A1 of US.Summarized the general strategy that is used for synthetic formula III, IIIA and IIIB compound in the scheme 17, it comprises three parts: (1) is the material construction bicyclic system with pyridine or pyrazoles, (2) connection-R 4-R 5Described ring system is further modified in group and (3).
Importantly, those skilled in the art should be realized that, the order of construction effect might not be (1)-(2)-(3), and these construction effect can exchange mutually, as long as reagent can be compatible between the functional group that is used for certain point in specifying under this situation.
Scheme 17
And as shown in Figure 5, formula 1,2,3 or 4 starting material and intermediate can exist with the form of tautomer, and two kinds of forms are not used in this patent with making any distinction between.
Figure GSA00000083249102201
Fig. 5
1. Synthesizing of pyrazolo [3,4-d] pyrimidine
1.1 with the pyrimidine is that raw material is synthetic Pyrazolo[3,4-d] pyrimidine
Figure GSA00000083249102202
Scheme 18
As summarizing in the scheme 18, formula 3 compounds can be prepared by pyrimidine.For example:
Method 1.1.1
Handle 2-amino-4 with hydrazine, 6-two chloro-pyrimidine-5-formaldehydes (formula 1) then easily make R 6For-Cl, R 7For-NH 2And R 3Be formula 3 compounds of-H, referring to, F.Sela, Heterocycles1985,23,2521; F.Seela, Helv.Chim.Acta 1986,69, and 1602; And R.O.Dempcy, WO 03/022859.
Method 1.1.2
Also do not report R before 6For-Cl, R 7For-NH 2And R 3Formula 3 compounds for alkyl, aryl or heteroaryl.It can make by in two steps formula 1 compound being converted into formula 5 compounds: i) to the nucleophilic addition(Adn) of carbonyl; The ii) alcohol of oxidation gained.In step subsequently, by formula 5 compounds being converted into formula 3 compounds with hydrazine or the reaction of its Equivalent.
Method 1.1.3
Handle nitrile with hydrazine and can obtain R 3For-NH 2Formula 3 compounds (referring to A.M.El-Reedy, Phosph, Sulf, Silic, 1989,42,231).
With the nitrile of hydrazine processing formula 6, hydrolysis can obtain R more afterwards 3Formula 3 compounds (referring to Ciba, patent UK 884,151 (1961)) for OH.
Method 1.1.4
Acid, ester and the activatory ester (or its Equivalent) of handling formula 7 with nitrile can obtain R 3Formula 3 compounds (Ciba, patent UK 884,151 (1961)) for OH.
1.2. With the pyrazoles is also [3,4-d] pyrimidine of raw material synthesizing pyrazole
Formula 3 compounds can also be made (scheme 19) by the pyrazoles of formula 2.Have various formation 6-unit ring method (for example, R.J.Bontems, J.Med.Chem, 1990,33,2174 and reference wherein).For example:
Scheme 19
Can handle R with Ph-CO-NCS 13For-CONH 2And R 14Be NH 2Formula 2 compounds, to obtain R 6Be OH and R 7Be NH 2Formula 3 compounds (F.Babin, J.Heterocycl.Chem.1983,20,1169).
Can handle R with thiocarbamide or guanidine 13For-CN and R 14Be NH 2Formula 2 compounds, to obtain R 6Be NH 2And R 7Be NH 2Formula 3 compounds (H.Kosaku, Heterocycles, 2001,55,2279).
Can be with CS2 or EtOCS 2K handles R 13For-CONH 2And R 14Be NH 2Formula 2 compounds, to obtain R 6Be OH and R 7Formula 3 compounds (S.M.Bennett, J.Med.Chem.1990,33,2162) for SH.
2. -R 4 -R 4 Pulsating combination
2.1. the alkylation of formula 3 compounds
At alkali K for example 2CO 3, NaH, Cs 2CO 3, DBU etc. existence under, exist/do not have catalyzer for example NaI, KI, (B u) 3Under the condition of NI etc., for example among DMF, THF, the DMSO etc., use for example L of electrophilic reagent at polar solvent 1-R 4-R 5(L wherein 1Be leavings group) (referring to scheme 20) can be with formula 3 alkylations.Leavings group includes but not limited to that for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate, triphenyl phosphorus (generate, for example PPh under the Mitsunobu condition 3/ DEAD) etc.(referring to Kasibhatla, PCT publication number WO 03/037860).
Figure GSA00000083249102221
Scheme 20
2.2. wherein-L 1Electrophilic reagent L for leavings group 1-R 4-R 5With nucleophilic reagent NH 2-R 4-R 5Preparation.
2.2.1. the benzylic type electrophilic reagent is synthetic:
Benzylic type electrophilic reagent (Fig. 2 formerly).L 1Be NH 2Corresponding amine can pass through prepared in various methods, for example use ammonia by L 1Be leavings group, for example the compound of chlorine, bromine, iodine, tosylate, methanesulfonate etc. perhaps prepares with repeated hydrogenation after the sodiumazide.
2.2.2. pyridylmethyl type electrophilic reagent is synthetic:
Pyridylmethyl electrophilic reagent (Fig. 3 formerly) can be by many method preparations of reporting in the document, and it comprises those documents that limit among the III.A.2.2.2..
3. The further modification of ring system
3.1.R 1Functional group change mutually
Can adopt standard conditions POC 13, POBr 3Deng, there is being/do not having for example Et of alkali 3N, N, accelerine, (i-Pr) 2Existence such as NEt and have/do not have for example BnEt of catalyzer 3N +Cl -Under the condition that exists, at polar solvent CH for example 3CN, CH 2C 12Deng in, with R 1For the formula III A compound of-OH is converted into halogenide.Methods involving includes but not limited to SOC 12/ DMF (M.J.Robins, Can.J.Chem.1973,12,3161), PPh 3/ CC 14(L.De Napoli, J.Chem.Soc.Perkin Trans 1,1994,923), HMPT/CC 14Or HMPT/NBS (E.A.Veliz, Tetrahedron Lett, 2000,41,1695) or PPh 3/ I 2(X.Lin, Org.Letters, 2000,2,3497).
By Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO for example 2/ H +, NOBF 4, RONO) and halogenic donator (for example, BF 4-, CuX 2, SbX 3), wherein X is a halogen, can be with R 1For-NH 2Formula III A compound be converted into halogenide.
R 1For the formula III A compound of alkyl can be by R 1Formula 3 compound (A.Holy, J.Med.Chem.1999,42,2064) for halogen and trialkylaluminium or dialkyl group zinc.
Use standard reagent, for example NH 3, NaOH, thiocarbamide, RO -, RS -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +), wherein R is a low alkyl group, can be with R 1For halid formula III A compound is converted into R 1For-NH 2,-OH ,-SH ,-OR ,-compound of SR.
3.2.R 2Functional group change mutually
Can be with R 2For-NH 2The temporary protection of formula III A compound get up, for example become acid amides (Ac 2O, PivCl, (tBoc) 2O) or carbonamidine (DMF-DMA).
By Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO for example 2/ H +, NOBF 4, RONO) and halogenic donator (BF for example 4 -, CuX 2, SbX 3), wherein X is a halogen, can be with R 2For-NH 2Formula III A compound be converted into halogenide.
Use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt the catalyzer (for example Pd, Ni, Cu, Lewis acid, H+) can be with R 2For halid formula III A compound is converted into R 2For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound.
R 2For the formula I compound of-SH can be converted into halogenide (Br 2).It can also oxidized (for example, H 2O 2) and handle to obtain-NH with amine 2Group (S.M.Bennett, J.Med.Chem.1990,33,2162).
R 2Be sulfide, for example the formula III A compound of MeS-can be converted into sulfone, for example MeSO 2 -, and by nucleophilic reagent, NH for example 3Or NH 2-NH 2, N 3-, CN-replaces.
3.3.R 3Functional group change mutually
R 3For the formula III A compound of H can be converted into R 3Formula III A compound (for example, NCS, NBS, NIS, Br for halogen 2, ICl, I 2/ KOH) (referring to F.Seela etal, Helv.Chim.Acta 1999,82,105).
Can be by the catalytic reaction of Pd-to R 3For the formula III A compound of halogen carries out functionalized ((a) Sonogashira coupling: E.C.Taylor etc., Tetrahedron, 1992,48,8089.(b) carboxylation: J.W.Pawlik, J.Heterocycl.Chem.1992,29,1357 (c) Suzuki coupling: T.Y.I Wu, Org.Lett., 2003,5,3587), perhaps addition (for example, the hydrazine by nucleophilic reagent, B.M.Lynch, Can.J.Chem.1988,66,420).
Use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +) can be with R 3For halid formula I compound is converted into R 3For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound.
Can be to R 3For the formula III A compound of MeO carries out demethylation, to generate R 3Formula III A compound (J.D.Anderson, J.Heterocycl.Chem., 199027,439) for OH.
3.4.R 5Further modification
R 5Especially can be as required when it is aryl or heteroaryl for example palladium coupling by halogenation, nitrated, halogen, pay-reactions such as Ke alkylation/acylations are by further modification; perhaps these modification can also be carried out before alkylation; referring to Jerry March, AdvancedOrganic Chemistry.Can also use for example H of various oxygenants 2O 2, O 3, MCPBA etc., at polar solvent CH for example 2Cl 2, CHC 13, CF 3Among the COOH etc. hetero-aromatic ring is oxidized to its corresponding N-oxide compound.Referring to Jerry March, Advanced Organic CXlemistry, 4 ThVersion, 19 chapters.The example of various modification is pointed out in scheme 21.
Figure GSA00000083249102251
Scheme 21
4. The variation of Build Order
As mentioned above, make up synthetic (2) R of reaction (1) bicyclic system 5-R 4The connection of-part and the further modification of (3) ring system are not to carry out with the order of (1)-(2)-(3), and it can advantageously carry out with different order.
For illustrative purposes, scheme 6 has shown a kind of building-up process of supposition, and wherein Build Order is not (1)-(2)-(3) but (1)-(3)-(2).
At first prepare bicyclic system, then it is modified, connect R by alkylation at last 5
Figure GSA00000083249102252
Scheme 22
For illustrative purposes, scheme 23 has shown a kind of building-up process of supposition, and wherein Build Order is not (1)-(2)-(3) but (2)-(1)-(3).At first pass through the nucleophilic substitution of aromatic ring with R 5Group is connected on the pyrimidine, makes up bicyclic system then, is converted to formula III A compound mutually through a series of functional group at last.
Figure GSA00000083249102261
Scheme 23
And, if R for example 5Be pyridine, then can before or after alkylation, be translated into the N-oxide compound.
E. Synthesizing of formula IV compound (triazolo pyrimidine and relevant analogue)
Formula IV of the present invention and IVA compound (referring to scheme 24) can synthesize by known the whole bag of tricks in the affiliated field, comprise for example Parkanyi, J.Heterocyc.Chem., 1990,27 (5), 1409-13; Beauchamp, U.S. patent 4,714,701,1987; Meier, U.S. patent 5,204,353,1993.Gillespie，WO?02/055083；Peterson，J.Med.Chem.，1990，33(4)，1214-19。Summarized general synthesis strategy in the scheme 1, it comprises three parts: (1) is the material construction bicyclic system with pyrimidine or 1,2,3-triazoles, and (2) connect R 5-R 4Described ring system is further modified in-group and (3).
Importantly,, those skilled in the art can recognize that the order of structure might not be (1)-(2)-(3), these construction effect can exchange mutually, can not produce incompatible phenomenon as long as specify between the functional group that is used for certain point under reagent and this situation.
Figure GSA00000083249102271
Scheme 24
Formula 1,2 and is not described two kinds of forms in this manual or/and 4 starting material and/or intermediate can exist with the form of tautomer with making any distinction between.
1. By pyrimidine synthesis type IV compound
1.1 Method 1
With excessive halogenating agent, for example POCl 3, oxalyl chloride or PC 15With reagent preparation MDF for example, to commercially available, R 9For-OH or halogen, R 10For amino or protected amino maybe can be converted into amino any group (for example SMe), R 11For H or-NO 2, R 12Handle for the substituted pyrimidines compound (referring to scheme 5) of the formula I of-Cl, obtain R 9Be halogen and R 12Be the formula IVA compound of halogen, afterwards at organic bases Et for example 3N, (i-pr) 2NEt exists down, at solvent for example among EtOH, the tBuOH etc., with nucleophilic reagent NH for example 2-R 4-R 5Carry out halogen and replace and to obtain formula 2 compounds, thus compound that can preparation formula IVA.Use zinc and formic acid or SODIUM HYDROSULPHITE sodium reduction R then 11For-NO 2Formula 2 compounds, obtain R 11For-NH 2Formula 2 compounds, referring to Dempcy, the open No.2003/0078413A1 of U.S..Can for example among the HCl, use alkali metal nitrites salts, for example NaNO at mineral acid then 2Carry out diazotization, carry out the compound that the original position cyclisation comes preparation formula IVA afterwards.Referring to Beauchamp, U.S. patent 4,714,701; Meier, U.S. patent 5,204,353.These compounds of formula IVA can carry out modification further as required.
Figure GSA00000083249102281
Scheme 25
Can for example among the HCl, use diazonium salt, at mineral acid for example by 4-chloroaniline and NaNO 2The 4-chloroaniline diazonium salt that makes is handled R 11Be formula 2 compounds of H, to obtain pyrimidine 5-azo-analogue, it can be obtained R by zinc powder reduction in EtOH/AcOH (1: 1) solution 11For-NH 2Formula 2 compounds, referring to Meier, U.S. patent 5,204,353.
1.2 Method 2
Figure GSA00000083249102282
Scheme 26
Equally, by commercially available, R 9For-OH or halogen, R 10For amino or protected amino maybe can be converted into amino any group (for example SMe), R 11And R 12For-NH 2The replacement diaminopyrimidine compounds (referring to scheme 26) of formula 1, then obtain formula 4 compounds according to the diazotisation methods of describing in the method 1 before, thus can preparation formula IVA compound.Can be at alkali K for example 2CO 3, NaH, Cs 2CO 3, DBU etc. existence under, exist/do not have halogenide for example NaI, KI, (Bu) 3Under the condition of NI etc., for example among DMF, THF, the DMSO etc., use for example L of electrophilic reagent at polar solvent 1-R 4-R 5(L wherein 1Be leavings group) formula 4 compounds are carried out alkylation.Leavings group includes but not limited to, for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate etc.Referring to Kasibhatla, PCT publication number WO 03/037860.Can also use the Mitsunobu alkylation conditions, use L 1L for hydroxyl 1-R 4-R 5, by formula D compound formula I compound.Referring to Kozai, Chem.Pharm.Bull., 1999,47 (4), 574-575.
2. By triazole synthesis type IV compound
As shown in scheme 27, formula IVA compound can also be by the triazole preparation that replaces.Therefore, at alkali for example KOH, NaOH, K 2CO 3, NaH, Cs 2CO 3, DBU etc. exists down, having/do not having halogenide for example NaI, KI, (Bu) 3Under the condition that NI etc. exist, for example among DMF, THF, the DMSO etc., use for example L of electrophilic reagent at polar solvent 1-R 4-R 5(L wherein 1Be leavings group), to R 14For-NH 2, R 13For-C (O) NH 2And R 15For formula 4 compounds (commercially available) of H carry out alkylation.In order to obtain formula 6 compounds, leavings group includes but not limited to for example halogen, trifluoromethanesulfonic acid root, tosylate, methanesulfonate etc.Use document Alhede, J.Org.Chem., 1991,2139 and the reference wherein quoted in many methods of reporting can realize ring closure, thereby obtain R 1Formula I compound for-OH.As discussed previously, use POC 13These compounds can be converted into R 1Formula I compound for-Cl.Alternatively, can also be as Chowdhury, J.Med.Chem.1999, the description in 42,4300, by reacting with the guanidinesalt hydrochlorate, and by R 14For-OH or halogenide, R 13For formula 3 compounds of-C (O) OEt make up.
Figure GSA00000083249102291
Scheme 27
3. Wherein-L 1 Electrophilic reagent L for leavings group 1 -R 4 -R 5 With nucleophilic reagent NH 2 -R 4 -R 5 Preparation
Benzylic type electrophilic reagent (Fig. 2 before) can prepare according to the description among the III.A.2.2.1.
Synthesizing of pyridylmethyl type electrophilic reagent:
Can prepare picolyl type electrophilic reagent (Fig. 3 before) according to many methods of reporting in the document, described document comprises the document that limits among the III.A.2.2.2.
In autoclave, use ammonia treatment R down in 20-160 ℃ 4-R 5-L 1, repeated hydrogenation after perhaps handling with sodiumazide then obtains compound R 4-R 5-NH 2, L wherein 1Be leavings group, for example chlorine, bromine, tosylate, methanesulfonate etc.
4. The further modification of ring system
Depend on the uncompatibility between the already present functional group, can carry out these modification in any stage.
4.1 R 1 Functional group change mutually
Adopt standard conditions POC 13, POBr 3Deng, there is being/do not having for example Et of alkali 3N, N, accelerine, (i-Pr) 2NEt etc. and have/do not have for example BnEt of catalyzer 3N +Cl -Condition under, at polar solvent CH for example 3CN, CH 2C 12Deng in, can be with R 1For the formula IVA compound of-OH is converted into halogenide.Methods involving includes but not limited to SOC 12/ DMF (M.J.Robins, Can.J.Chem.1973,12,3161), PPh 3/ CC 14(L.De Napoli, J.Chem.Soc.Perkin Trans 1,1994,923), HMPT/CC 14Or HMPT/NBS (E.A.Veliz, Tetrahedron Lett, 2000,41,1695) or PPh 3/ I 2(X.Lin, Org.Letters, 2000,2,3497).
By Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO 2/ H +, NOBF 4, RONO) and halogenic donator (BF 4-, CuX 2, SbX 3), can be with R 1For-NH 2Formula IVA compound be converted into halogenide.
R 1For the formula IA compound of alkyl can be by R 1Formula 4 compound (A.Holy, J.Med.Chem.1999,42,2064) for halogen and trialkylaluminium or dialkyl group zinc.
Use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +), can be with R 1For halid formula IA compound is converted into R 1For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound (for example, B.G.Ugarkar, J.Med.Chem.2000,43,2883-2893 and 2894-2905).
Can handle R with amine 1Be the formula IVA compound of halogen or another leavings group, to generate R 1Be NH 2Formula IVA compound (F.Seela, Liebigs.Ann.Chem.1985,315).
4.2. R 2 Functional group change mutually
Can be with R 2For-NH 2The temporary protection of formula IVA compound get up, for example become acid amides (Ac 2O, PivCl), carbamate (tBoc) 2O or amidine (DMF-DMA).
Can pass through Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I), adopt nitrosyl reagent (NaNO 2/ H +, NOBF 4, RONO) and halogenic donator (BF 4 -, CuX 2, SbX 3, wherein X is a halogen), with R 2For-NH 2Formula IA compound be converted into halogenide.
Use standard reagent, for example NH 3, NaOH, thiocarbamide, R 8O -, R 8S -, adopt or do not adopt catalyzer (for example Pd, Ni, Cu, Lewis acid, H +), can be with R 2For halid formula IVA compound is converted into R 2For-NH 2,-OH ,-SH ,-OR 8,-SR 8Compound.
R 2For the formula IA compound of-SH can be converted into halogenide (Br 2).It can also oxidized (for example, H 2O 2) and handle to obtain NH2 group (S.M.Bennett, J.Med.Chem.1990,33,2162) with amine.
R 2Be sulfide, for example the formula IVA compound of MeS-can be converted into sulfone, for example MeSO 2 -, and by nucleophilic reagent, NH for example 3Or NH 2-NH 2, N 3-, CN-replaces.
4.3 R 5 Further modification
R 5Especially can be as required when it is aryl or heteroaryl for example palladium coupling by halogenation, nitrated, halogen, pay-reactions such as Ke alkylation/acylations are by further modification; perhaps these modification can also be carried out before alkylation; referring to Jerry March, AdvancedOrganic Chemistry.Can also use for example H of various oxygenants 2O 2, O 3, MCPBA etc., at polar solvent CH for example 2C 12, CHC 13, CF 3Among the COOH etc. hetero-aromatic ring is oxidized to its corresponding N-oxide compound.Referring to Jerry March, Advanced Organic CXlemistry, 4th version, 19 chapters.The example of various modification is pointed out in scheme 28.
And, if R 5For example be pyridine, then it can be converted into the N-oxide compound before or after alkylation.
Figure GSA00000083249102311
Scheme 28
IV. Pharmaceutical composition, dosage and administering mode
The present invention relates to the heterocycle material, especially the pyrazolopyrimidine of formula A, I-IV and related analogs thereof, with and polymorphic form, solvate, ester, tautomer, diastereomer, enantiomer, pharmacy acceptable salt and prodrug thereof, be used for the treatment of or prevent the clinical application of HSP90-dependent form disease.For example, such as the illness of inflammatory diseases, infection, autoimmune disorder, apoplexy, local asphyxia, cardiac conditions, nervous disorders, fibrosis illness, proliferative disorders, tumour, leukemia, vegetation, cancer, cancer knurl, metabolic trouble and malignant disease.The fibrosis illness includes but not limited to scleroderma, polymyositis, system's lupus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis and pulmonary fibrosis.
The invention is characterized in the pharmaceutical composition of formula A, I-IV compound or its polymorphic form, solvate, ester, tautomer, enantiomer, diastereomer, pharmacy acceptable salt or its prodrug and one or more pharmaceutical excipients that comprise aforementioned any aspect and embodiment.
Those of ordinary skill in the field know the preparation and the medicine-feeding technology that can be used for The compounds of this invention and method, for example, as Goodman and Gilman, The Pharmacological Basisof Therapeutics, (existing), Pergamon with version; And Remington ' s, PharmaceuticalSciences (existing), Mack Publishing Co., Easton, the argumentation among the PA with version.
Can be individually dosed with compound in the methods of the invention, perhaps, in pharmaceutical compositions, combine administration with pharmaceutically acceptable carrier, excipient or thinner according to the pharmacy routine of standard.Described compound can oral or enteron aisle external administration, comprises through intravenously, intramuscular, intraperitoneal, subcutaneous, rectum and topical routes.
For example, can be with treatment of the present invention or pharmaceutical composition topical to the zone that needs treatment.This can pass through, such as but not limited to part in surgical procedures inculcate, topical application for example cream, ointment, injection, conduit, or transplant and realize that described transplanting is for example made by porous, atresia or colloidal material, this material comprises film, for example sialastic film or fiber.Can also go up and come administration in the position of the tissue of tumour or knurlization or pre--knurlization (or before position) by direct injection.
Further, compound of the present invention or composition can also for example transport that (referring to, Langer for example, Science 1990,249,1527-1533 at capsule in the liposome; Treat etc., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., 353-365 page or leaf, 1989).
Can also in controlled delivery systme, transport with in the methods of the invention compound and pharmaceutical composition.In one embodiment, can use pump (referring to, Sefton, 1987, CRCCrit.Ref.Biomed.Eng.14:201; Surgery such as Buchwald, 1980,88,507; N.Engl.J.Med.1989 such as Saudek, 321, (574)).In addition, the controlled release system can also be placed on the treatment target spot near.(referring to, Goodson, Medical Applications ofControlled Release, 1984,2,115-138).
Can also contain the promising activeconstituents that is fit to the form that orally uses with in the methods of the invention pharmaceutical composition, for example be tablet, lozenge, sugared shallow lake, water-based or oily suspensions, dispersible powder or particle, emulsion, hard or soft capsule or syrup or elixir.The composition that intention orally uses can prepare according to any method known in the art, that be used for pharmaceutical compositions, and this composition can contain one or more reagent that is selected from sweeting agent, sweetener, tinting material and sanitas, in order to medicinal exquisiteness and good to eat preparation to be provided.Tablet contains activeconstituents and is mixed with and is suitable for preparing tablet, atoxic pharmaceutically acceptable excipient.These excipient can for, for example, inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agent are as Microcrystalline Cellulose, croscarmellose sodium, W-Gum or Lalgine; Tackiness agent, for example starch, gelatin, polyvinyl-pyrrolidone or gum arabic, and lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can carry out dressing to it for uncoated tablets or with known technology, in order to taste or the delay disintegration and the absorption in gi tract of masking agents, thereby provides long-time interior continuous action.For example, can suitably use water-soluble taste masked material, for example hydroxypropyl methyl-Mierocrystalline cellulose or hydroxy propyl cellulose, the material of perhaps delaying time, for example ethyl cellulose or cellulose acetate butyrate.
The preparation that is used to orally use can also be activeconstituents and inert solid diluent, the hard gelatin capsule that mixes of lime carbonate, calcium phosphate or kaolin for example, perhaps be activeconstituents and water-soluble carrier such as polyoxyethylene glycol or oily medium, the soft gelatin capsule that gets up of peanut oil, whiteruss or mixed with olive oil for example.
Waterborne suspension contains active substance and is mixed with the excipient that is suitable for preparing waterborne suspension.This excipient is a suspension agent, for example carboxylic acid methyl sodium cellulosate, methylcellulose gum, hydroxypropyl methyl-Mierocrystalline cellulose, sodium alginate, polyvinyl-pyrrolidone, Tragacanth and Sudan Gum-arabic; Dispersion or wetting agent can be the phosphatide of natural-formation, Yelkin TTS for example, the perhaps condensation product of oxirane and lipid acid, polyoxyethylene stearic acid ester for example, the perhaps condensation product of oxyethane and long chain aliphatic alcohol, 17 ethene-oxygen hexadecanol for example, perhaps oxyethane and condensation product derived from the partial ester of lipid acid and hexitol, polyoxyethylene sorbitol monoleate for example, perhaps oxyethane and condensation product, for example polyethylene sorbitanic monoleate derived from the partial ester of lipid acid and hexitan.Waterborne suspension can also contain one or more sanitass, for example ethyl p-hydroxybenzoate, n-propyl, one or more tinting materials, one or more sweetener and one or more sweeting agents, for example sucrose, asccharin or aspartame.
Oily suspensions can be by being suspended in vegetables oil with activeconstituents, for example peanut oil, sweet oil, sesame oil or cocounut oil, and perhaps mineral oil for example comes preparation in the whiteruss.Oily suspensions can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent, for example foregoing those materials, and sweetener are in order to provide good to eat oral preparations.These compositions can be by adding antioxidant, and for example butylated BHA or alpha-tocopherol are stored.
But be suitable for activeconstituents being provided and being mixed with wetting agent, suspension agent and one or more sanitass by adding dispersed powders and the particle that water prepares waterborne suspension.Suitable dispersion agent or wetting agent and suspension agent are as already mentioned above shown in those materials.Can also contain other excipient, for example sweeting agent, sweetener and tinting material.These compositions can be by adding antioxidant, and for example xitix is stored.
With in the methods of the invention compound and pharmaceutical composition can also for water-Bao-oil emulsion form.Oil phase can be vegetables oil, for example sweet oil or peanut oil, or mineral oil, for example mixture of whiteruss or these materials.Suitable emulsifying agent can be the phosphatide of natural-formation, for example soybean lecithin and derive and the ester or the partial ester that come, for example sorbitanic monoleate by lipid acid and hexitan, and the condensation product of described partial ester and oxyethane, for example polyoxyethylene sorbitanic monoleate.Emulsion can also contain sweeting agent, sweetener, sanitas and antioxidant.
Syrup and elixir can with sweeting agent, for example glycerine, propylene glycol, Sorbitol Powder or sucrose preparation together.This preparation can also contain lubricant, sanitas, sweetener and tinting material and antioxidant.
Pharmaceutical composition can be aseptic injectable aqueous solutions form.Acceptable carrier and operable solvent are water, Ringer's solution and isotonic sodium chlorrde solution.
Sterile injectable preparation can also be the water-Bao-oil microemulsion liquid of sterile injectable, and wherein activeconstituents is dissolved in the oil phase.For example, can at first activeconstituents be dissolved in the mixture of soybean oil and Yelkin TTS.Then oil solution is incorporated in the mixing of water and glycerine, and handles to form microemulsion.
Can Injectable solution or microemulsion be incorporated in patient's the blood flow by local pill injection.Alternatively, can advantageously give drug solns or micro emulsion by this way, thereby make compound of the present invention remain the constant circulation composition.In order to keep this constant concentration, can use successive intravenously e Foerderanlage.The example of this device is Deltec CADD-PLUS TMType 5400 venous pumps.
Pharmaceutical composition can be for being used for the sterile injectable water-based or the oleagenous suspension of intramuscular and subcutaneous administration.This suspension can use suitable above-mentioned dispersion agent or wetting agent and suspension agent to come preparation according to known technique.Sterile injectable preparation can also for outside nontoxic, enteron aisle-sterile injectable solution or suspension in acceptable diluent or the solvent, for example be the solution in 1,3 butylene glycol.In addition, aseptic fixed oil is often used as solvent or suspension medium.The fixed oil of any gentleness may be used to this purpose, comprises synthetic list-or two glyceryl ester.In addition, lipid acid, for example oleic acid also can be used in the preparation of injectable formulation.
Can also be used for the described medicament of rectal administration with the form of suppository with in the methods of the invention The compounds of this invention.These compositions can be by inhibitor and suitable preparing mixing of non-irritating excipient, and wherein said non-irritating excipient is solid at normal temperatures, but is liquid under rectal temperature, therefore discharges medicine in the internal rectum thawing.This material comprises the mixture of the fatty acid ester of theobroma oil, glycerin cement, hydrogenated vegetable oil, various molecular weight polyethylene glycol and polyoxyethylene glycol.
Use for the part, can use cream, ointment, jelly, solution or the suspension etc. that contain The compounds of this invention or composition.As used in this article, topical application can comprise mouth wash shua and gargarism.
Can with form administration in the nose, perhaps use skin fritter known to a person of ordinary skill in the art via carrier and e Foerderanlage in the suitable nose with in the methods of the invention compound via the skin administration.For the situation with the form administration of skin delivery system, dosed administration certainly should be continuously but not is interrupted and carries out in whole dosage regimen process.
Method of the present invention, compound and composition can also be known with other, because of it therapeutical agent that special treatment purposes of the illness of being treated is selected is used in combination.For example, compound of the present invention can be used in combination with known anticancer and cytotoxic agent.In addition, method of the present invention and compound can also be used in combination with the part inhibitor of other signal pipeline, and wherein said letter transmission approach couples together cell surface growth factor receptors and the outgrowth nuclear signal of trigger cell.
Method of the present invention can also be used for suppressing other medicament that thereby growth of tumour cell and intrusion take place to suppress blood vessel, described other medicament includes but not limited to the vegf receptor inhibitor, comprises ribozyme and anti-sensitiser, angiostatin and the Endostatin of target vegf receptor inhibitor.
The antineoplastic agent that can be used in combination with The compounds of this invention and method comprises alkylating agent, anti--the metabolism agent, table podophyllotoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/anti--hormonotherapy medicine and hemopoieticgrowth factor usually and suitably.The exemplary types of antitumour drug comprises anthracene nucleus class, Vinca medicine, mitomycin, bleomycin, cytotoxin nucleosides, Epsilon, discodermolide, pteridine, diynenes and podophyllotoxin.Useful especially member for example comprises in the type, carminomycin, Rubomycin C, aminopterin, methotrexate, methopterin-A, carrene, ametycin, porfiromycin, 5 FU 5 fluorouracil, the happy disease of 6-are peaceful, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllin derivative, for example etoposide, etoposide phosphoric acid salt or Vumon, phenylalanine, vincaleucoblastine, vincristine(VCR), leurosidine, desacetyl vinblastine amide, leurosine, taxol etc.Other available antitumour drug comprises female Moses spit of fland, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, phenylalanine, altretamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, the altheine enzyme, camptothecine, CPT-11, the holder pool is for surveying (topotecan), ara-C, bicalutamide, flutamide, Leuprolide, pyrido benzindole (pyridobenzoindole) derivative, Interferon, rabbit and interleukin.
When compound of the present invention or composition were delivered medicine to the human receptor, per daily dose should determine that this dosage changes according to age, body weight and the reaction of individual patient and the seriousness of patient symptom usually by the prescriber usually.
In an example use, with an amount of compound administration in accepting cancer, the Mammals of breast cancer treatment for example.The dosage of every day is generally about 0.01mg/kg body weight-Yue 100mg/kg body weight (single or divided dose administration), more preferably is at least about 0.1mg/kg body weight.Specific therapeutic dose can comprise that the about 1000mg compound of for example about 0.01mg-preferably includes, the about 1000mg of for example about 1mg-.In the preparation of unitary dose, according to application-specific, the amount of active compound can be at about 0.1mg-1000mg, and preferably about 1mg-300mg more preferably changes in the 10mg-200mg or adjusting.Dosage should be according to the specific IC of compound used therefor 50The value and the clinicist that pays a home visit are considering each factor, the judgement of making under for example healthy, the body weight and the situation at age and changing.Described compound be not independent activeconstituents in conjunction with in using, compound that can the administration less amount, and still have treatment or preventive effect.
Preferably, pharmaceutical preparation is a unit dosage form.In this form, preparation is subdivided into and contains suitable amount of active ingredients, for example reaches the unit dose of the significant quantity of desired purpose.
Used reagent dosage can change according to patient's needs and sanatory seriousness.Determine that at particular case suitable dosage is in the technical scope of this area.Adopt the smaller dose that is less than the compound optimal dose when usually, treatment begins.Afterwards, increase dosage with a small amount of form, until being issued to best effect in described situation.For convenience's sake, if wish, then can in the daytime whole per daily dose distributed and with form administration repeatedly.
With The compounds of this invention and composition in the methods of the invention, and if you are using, other chemotherapeutic agents and/or radiotherapeutic dosage and frequency, should be according to the clinicist that pays a home visit (doctor's) judgement, regulate in the situation of the severity of disease of having considered for example age, symptom and patient sizes and treatment.
Chemotherapeutic agents and/or radiotherapy can be come administration according to treatment plan well known in the art.To those skilled in the art, apparently, chemotherapeutic agents and/or radiotherapeutic administration can change according to the disease of being treated and chemotherapeutic agents and/or the radiotherapy known effect to this disease.And, according to the knowledge of skilled clinician, treatment plan (for example, dosage and number of times) can also in view of viewed drug treatment medicament (promptly, antitumour drug and radiation) to patient's effect, and in view of viewed disease to the reaction of drug treatment medicament and change.
And, compound of the present invention usually needn't with chemotherapeutic agents in same administered in pharmaceutical compositions, and may be because different physics and chemical propertys, it is according to different administrations.For example, compound can be taken orally, and producing and to keep its good blood levels, and chemotherapeutic agents can intravenous administration.Determining of administering mode, and if possible, in same pharmaceutical composition, carry out the rational of administration and determine, fully in the ken of skilled clinician.Initial administration can be carried out according to known in the art, the scheme well of formulating, and changes dosage, administering mode and administration number of times based on observed effect by skilled clinicist afterwards.
The special selection of compound (suitable, chemotherapeutic agents and/or radioactive rays) should be depended on visiting physician's diagnosis, and it is to the judgement of patient symptom and suitable treatment plan.
Depend on character, patient's the symptom of proliferative disease and actual selection, combine administration (promptly with described compound, in single treatment plan) chemotherapeutic agents and/or radioactive rays, compound of the present invention (suitable words, chemotherapeutic agents and/or radioactive rays) can be jointly (for example, simultaneously, simultaneously basic or in same treatment plan) or administration successively.
In conjunction with in using and using, described compound and chemotherapeutic agents and/or radioactive rays needn't be simultaneously or basic administration simultaneously, and the initial order of administration of described compound and chemotherapeutic agents and/or radioactive rays may be unimportant.Therefore, at first administration compound of the present invention, administration chemotherapeutic agents and/or radioactive rays afterwards; Perhaps at first administration chemotherapeutic agents and/or radioactive rays, the compound of the present invention of administration afterwards.In independent treatment plan process, can repeat this alternative administering mode.After the disease of being treated and patient symptom are estimated, determining fully in the ken of skilled practitioners in the treatment plan process to the number of times of the order of administration of every kind of healing potion, repeat administration.For example, at first administration chemotherapeutic agents and/or radioactive rays, if when especially it is cytotoxic agent, administration compound of the present invention continues treatment then, if think favourable afterwards then administration chemotherapeutic agents and/or radioactive rays, or the like finish until treatment plan.
Therefore, according to practice and knowledge, in the process that continues treatment, on-the-job doctor can change each scheme that is used for the drug treatment compound according to the needs of individual patient.
The clinicist that pays a home visit is judging that under dosage treatment whether effectively the time, will consider the common good order and condition of patient and more definite illness, for example the actual inhibition of dwindling or shifting of the inhibition of disease-related indication alleviation, tumor growth, tumour.Whether the tumour size can be by standard method, and for example radioactivity research such as CAT or MRI scan and measure, and can use continuously measured to be delayed or even to reverse to judge growth of tumor.Disease-related symptoms, for example the improvement of the alleviation of pain and whole symptom can also be used to help to judge the validity of treatment.
V. In order to determine the test of HSP90 combination and downstream effect
Various external and in vivo test can be used for testing the effect of The compounds of this invention to HSP90.The test of the CBA of HSP90 and sense can be according to methods known in the art, replace with compound of the present invention and carry out.Chiosis etc., Chemistry ﹠amp; Biology 2001,8, and 289-299 has described some currently known methodss that can carry out this test.For example, use as geldanamycin or 17-AAG as HSP90 competitiveness binding inhibitors, useful compound or other competitive inhibitor are fixed on gel or the solid substrate, cultivate HSP90 in advance with other inhibitor, make pre-culturing mixt by gel or matrix, measure the amount that keeps or be not retained in the HSP90 on gel or the matrix then, this CBA that is carried out can be used for determining the relative HSP90 avidity of The compounds of this invention.
Can also estimate the downstream effect based on known, HSP90 to the function of various steroid receptors and signal-proteins (comprising for example Raf1 and HER2) and the inhibiting effect of stability.The compounds of this invention is induced these molecule generation dosage-dependency degraded, and it can use standard method to measure.The restraining effect of HSP90 also causes the rise of HSP90 and relevant chaperone protein, and similarly it also can be measured comes out.Can also measure anti-proliferative activity, suppress relevant form and functional segregation as measuring with HSP90 for various cancerous cell lines.
Known many methods dissimilar, that be used for determining protein concn and measurement or predict the protein level of cell and liquid sample in this area.Non-direct method comprises uses for example nucleic acid hybridization and the amplification of polymerase chain reaction (PCR).These methods are known for those of skill in the art, and at for example Sambrook, Fritsch; Maniatis MolecularCloning:A Laboratory Manual, 2 NdVersion, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989; Ausubel, etc., Current Protocols inMolecular Biology, John Wiley ﹠amp; Sons, New York, 1994, in discuss, and as the relative reactivity of the HER2/Neu in quantitative, detection and patient specimens in concrete application, for example referring to U.S. patent 4,699,877,4,918,162,4,968,603 and 5,846,749.Be the summary of operable two kinds of universal methods below.
Pair cell whether by overexpression or contain rising the HER2 level determine can use known antibody method, the immune absorption test (ELISA) of for example immune marking method, radioimmunoassay, western blotting, immunoprecipitation, enzyme-connection and utilization are at the deriving method of the antibody of HER2.As an example, use immunohistochemical test, for example DakoHercep TMTest can determine the HER2 in the breast cancer cell express (Dako Corp., Carpinteria, CA).Hercep TMTest is for being used for detecting the antibody staining test of HER2 in the overexpression of tumor tissues sample.This specific test is divided into four levels with the expression of HER2: 0,1,2 and 3, and the highest level that on behalf of HER2, level 3 express.Use as, Press for example, the Modern Pathology 2000,13 of M. etc., the automated cell imaging system of describing among the 225A (ACIS) can be strengthened accurate quantification.
Many cells systems or monoclonal antibody can be buied in various suppliers, perhaps can use known method, for example, as Harlow etc., Antibodies:A Laboratory Manual, 2 NdVersion; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1988, in description prepare.
Have very high cognation owing to reported between proteinic overexpression of HER2 and the amplification, therefore can also on nucleic acid level, determine the overexpression of HER2 its gene of encoding.Check its a kind of mode to be to use RT-PCR.The genome of HER2 and cDNA sequence are known.Specific dna primer can use standard, technique known to produce, and can be used for subsequently the template amplification of cell Already in.Its example is described in Kurokawa, H. etc., and Cancer Res.2000,60, among the 5887-5894.Can carry out stdn to PCR, thereby observe normal and abnormal cells, for example the quantity difference between cancer cells and the non-cancer cells.The known method that adopts, for example photodensitometry can be used for quantitatively and/or the nucleic acid level of relatively amplifying through PCR.
Similarly, can use fluorescent in situ hydridization (FISH) test and other test, for example Northern and/or Southern transfer printing.These tests depend on the nucleic acid hybridization between HER2 gene or mRNA and the corresponding nucleic acids probe, and wherein said nucleic acid probe can be according to designing with the identical or similar mode of above-mentioned PCR primer.Referring to, for example Mitchell MS and Press M.F.Oncol., Suppl.1999,12,108-116.For FISH, this nucleic acid probe can with fluorescence molecule, for example fluorescein and/or rhodamine cooperate, it does not preferably disturb hydridization, and its fluorescence can be measured after hydridization.Referring to, Kurokawa for example, H etc., Cancer Res.2000,60,5887-5894 (described have sequence 5 '-the specific nucleic acid probe of FAM-nucleic acid-TAMRA-p-3 ' sequence).The method of aforesaid ACIS-base can be used to make to be tested more quantification (dela Torre-Bueno, J. waits Modern Pathology 2000,13,221A).
Immunity and detection of nucleic acids can also be at the protein that is different from HSP90 and HER2, yet described protein will be affected to the response of HSP90 inhibition.
The following example only provides in the mode of explanation, and it does not limit the entire area and the spirit of invention.
Embodiment
I. The preparation of pyrrolopyrimidine and related analogs (formula I compound)
A. Material and method
Be used to generate the chemical reagent of following new product of the present invention all commercially available from, Aldrich Chemical Co. for example, Milwaukee, WI, the U.S..Otherwise then it prepares easily and is known for those of ordinary skills, and perhaps it has mentioned in this article and describes.
Final compound adopts preparation property TLC (silica gel usually
Figure GSA00000083249102411
Whatman PartisilPK6F) or flash chromatography (silica gel
Figure GSA00000083249102412
The EMD chemical), use EtOAc/ hexane or MeOH/CH 2Cl 2Come purifying as eluent.Use silica gel tlc plate (silica gel
Figure GSA00000083249102413
The EMD chemical) measures the Rf value.Use C 18 posts (Agilent Zorbax 300SB-C18; 5 microns; 4.6mm * 150mm) obtain analytical HPLC chromatogram.Used constant flow rate 1mL/ minute, the ratio of A is increased to 100% (t=7.00 minute) by 5% (t=0) linearity, thereby at solvent orange 2 A (0.1%TFA in the water) and solvent B (CH 30.5%TFA among the CN) applies gradient between.Usually at MeOH or CH 3Among the CN sample is diluted to 0.1-1mg/mL, and volume injected is generally 10 μ L.Coupled columns does not heat, and carries out UV at the 254nm place and detects.Record on Bruker Avance 400MHz spectrograph 1The H-NMR spectrogram.Use Beilstein Autonom 2.1 softwares to generate chemical name.
B. General step
1. The general step of preparation and conversion pyrrolo-[2,3-d] pyrimidine ring
General step 1.1: pyrrolo-[2,3-d] pyrimidine (R 0≠ OH) preparation
Figure GSA00000083249102421
Under 22-40 ℃ with 4-diamino-6-hydroxy pyrimidine (6mmol), AcONa (12mmol) and alpha-halogen aldehyde (6mmol) at CH 3CN (20mL) and H 2The suspension that forms among the O (20mL) stirs and spends the night, and then initial substance dissolves gradually, and desirable pyrrolo-[2,3-d] pyrimidine is precipitated out.Filter collecting precipitation thing and washing (water, acetonitrile, ether) and dry air ((a) C.J.Barnett, Org.Proc.Res.Develop.1999,3,184.(b)F.Seela，Liebigs?Ann.Chem.1987，15)。
General step 1.2: pyrrolo-[2,3-d] pyrimidine (R 0=OH) preparation
Figure GSA00000083249102422
With (2-amino-4,6-two chloro-pyrimidine-5-yl)-vinyl acetic monomer, R 5-R 4-NH 2And EtN (i-Pr) 2The suspension reflux 24h that in BuOH, forms, removal of solvent under reduced pressure subsequently.Then residuum is dissolved in CH 2C 12In, use saturated NaHCO 3Washing is also used Na 2SO 4Dry.Crude product is by preparation property TLC or flash chromatography (EtOAc/ hexane or MeOH/CH 2C 12) purifying, obtain pure pyrrolo-[3,4-d] pyrimidine-6-ketone.
General step 1.3: the alkylation of pyrrolo-[2,3-d] pyrimidine on the N-7 position
Figure GSA00000083249102423
With 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (1mmol), benzyl halide (1mmol) and K 2CO 3Or Cs 2CO 3(1-5mmol) suspension that forms in dry DMF (5mL) is heated to 40 ℃ and keep 3-10h.With preparation property TLC or flash chromatography (EtOAc/ hexane or MeOH/CH 2C 12) handle (EtOAc) and purifying, obtain the pure alkylating product in N-7 position.
General step 1.4: the aminomethylation of pyrrolo-[2,3-d] pyrimidine on the C-5 position
Figure GSA00000083249102431
The sealing test tube in 2-amino-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol, formaldehyde (2-5 equivalent) and HNR 9R 9The solution that (2-5 equivalent) forms in 80% acetum is heated to 60 ℃ and also experiences whole night, concentrates, at MeOH: CH 2C 12Saturated NaHCO is used in extraction in (1: 10) 3Washing also concentrates.Referring to H.Akimoto, J.Chem.Soc.Perkin Trans 1.1998,1637.
General step 1.5: pyrrolo-[2, the 3-d] pyrimidine-alkylation of 6-ketone on the C-5 position
Under-78 ℃, to pyrrolo-[2,3-d] add alkali in the solution that pyrimidine-6-ketone forms in THF, for example LDA, LHMDS or KHMDS, further add alkyl halide after 30 minutes, to obtain monoalkylation and bis-alkylated pyrrolo-[2,3-d] pyrimidine-6-ketone, it is by preparation property TLC or flash chromatography (EtOAc/ hexane or MeOH/CH 2C 12) purifying.
General step 1.6: the oxidation of pyrrolo-[2,3-d] pyrimidine on the C-5 position
Figure GSA00000083249102433
Reflux 2-amino-4-chloro-pyrrolo-[2,3-d] pyrimidine-6-ketone and SeO 2The solution that forms in dioxane is until finishing (1h), removal of solvent under reduced pressure subsequently.Crude product is through preparation property TLC or flash chromatography (EtOAc/ hexane or MeOH/CH 2C 12) purifying obtains pure 4-chloro-5-hydroxyl-2-imino--2,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone.
2. The general step of conversion pyridine ring
General step 2.1: the preparation of pyridine N-oxides
Cool off the solution of pyridine derivate (1mmol) in methylene dichloride or chloroform (5mL) with ice bath, divide three parts of processing with m-CPBA (1.1-3mmol), and make it be warming up to room temperature.Also use the NaOH aqueous solution with the dichloromethane extraction mixture, wash with water more afterwards.Dry (Na 2SO 4) and the concentrated pyridine N-oxides that obtains.
The preparation of general step 2.2:2-(acetoxy-methyl)-pyridine
With the vlil of 2-PICOLINE N-OXIDES (1.0mmol) in acetic anhydride (5mL) and lasting 0.5h.Handle (EtOAc), dry (MgSO 4), evaporation and with preparation property TLC or flash chromatography purifying, obtain 2-(acetoxy-methyl)-pyridine.
The preparation of general step 2.3:2-(hydroxymethyl)-pyridine
With 2-acetoxy-methyl-pyridine derivate and solid K 2CO 3The suspension that forms in methyl alcohol is heated to 50 ℃ and kept 5-30 minute.Evaporation, processing (EtOAc) and dry (MgSO 4), obtain 2-(hydroxymethyl)-pyridine.
The preparation of general step 2.4:2-(brooethyl)-pyridine
The solution that 2-(hydroxymethyl)-pyridine (1.0mmol) and triphenylphosphine (1.2mmol) are formed in methylene dichloride or chloroform (5mL) is cooled to 0 ℃.Drip CBr 4(1.5mmol) solution in methylene dichloride or chloroform, and under 0 ℃, stir gained mixture 0.5-1h.Handle afterwards and use the flash chromatography purifying, obtain 2-(brooethyl)-pyridine.
The preparation of general step 2.5:2-(amino methyl)-pyridine
Under 100 ℃ in MeOH with the 2-in the ammonia soln (chloromethyl)-pyridine derivate heated overnight, then it is carried out concentrating under reduced pressure, and with flash chromatography (MeOH/CH 2Cl 2) purifying, obtain 2-(amino methyl)-pyridine derivate.
The preparation of general step 2.6:2-chloropyridine
Stir POC down at 110 ℃ 132-(30mL) (hydroxymethyl)-pyridine (10g) suspension 1.5h.The toughening oil of gained is cooled in room temperature and the impouring frozen water (500g).With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation obtain the 2-chloropyridine, it is not purified just to use.
General step 2.7: the preparation of pyridinium salt
The heating pyridine solution dissolves until it in MeOH.Add the methanol solution of acid (1.0 normal for example HCl, MsOH), solvent evaporated obtains pyridinium salt.
3. The general step of conversion phenyl ring
General step 3.1: the halogenation of phenyl ring
Variant 1:Use Br under the room temperature 2The aromatics solution (the 1N solution among each AcOH and the AcONa) that (1.3 equivalent) processing forms in the slow agent of MeOH/THF/ acetic ester 5 minutes.On rotatory evaporator, remove excessive bromine and solvent.Handle (CHCl 3) and through flash chromatography, the bromobenzene that obtains wishing.
Variant 2: the solution that aromatics (7mmol) and n-halo succinimide (NCS, NBS or NIS, 1.06 equivalents) are formed in acetic acid (40mL) is heated to 40-90 ℃ and continue 0.3-1h.Evaporation, handle (EtOAc) and through flash chromatography, the benzene halide that obtains wishing.
C. The preparation of intermediate
Embodiment 1.2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
Figure GSA00000083249102451
According to general step 3.1, to 5-chloromethyl-1,2,3-trimethoxy-benzene carries out chlorination and obtains title compound with NCS.
1H-NMR(CDCl 3)：δ6.82(s，1H)，4.70(s，1H)，3.93(s，3H)，3.90(s，3H)3.87(s，3H)。
Embodiment 2.2-chloro-6-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine
Figure GSA00000083249102452
Step 1:2-chloromethyl-4-methoxyl group-3,5-lutidine-1-oxide compound
According to general step 2.1, to 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine carries out oxidation and obtains title compound.HPLC Rt:4.46 minute. 1H-NMR(CDCl 3)：δ8.05(s，1H)，4.93(s，2H)，3.77(s，3H)，2.37(s，3H)，2.24(s，3H)。
Step 2:2-chloro-6-chloromethyl-4-methoxyl group-3, the 5-lutidine
According to general step 2.6, use POCl 3Handle 2-chloromethyl-4-methoxyl group-3,5-lutidine-1-oxide compound obtains title compound.HPLC Rt:6.757 minute. 1H-NMR(CDCl 3)：δ4.64(s，2H)，3.79(s，3H)，2.35(s，3H)，2.33(s，3H)。
Embodiment 3.4-chloro-2-chloromethyl-3,5-dimethyl-pyridine
Figure GSA00000083249102461
According to general step 2.6 in identical mode, use POCl 3Handle 2-chloromethyl-3,5-lutidine-4-alcohol (Tarbit, etc., WO 99/10326) obtains title compound (74% productive rate).HPLC Rt:5.54 minute. 1H-NMR(CDCl 3)：δ8.24(s，1H)，4.71(s，2H)，2.48(s，3H)，2.36(s，3H)。
Embodiment 4.4-bromo-2-brooethyl-3,5-dimethyl-pyridine
According to any preparation 4-bromo-2-brooethyl-3 in following three kinds of methods, 5-dimethyl-pyridine:
Method 1
Figure GSA00000083249102462
Step 1:2,3,5-collidine-N-oxide compound
According to general step 2.1, by oxidation 2,3,5-collidine and obtain 2,3,5-collidine-N-oxide compound with 70% productive rate.HPLC Rt:3.96 minute. 1H-NMR(CDCl 3)：δ8.03(s，1H)，6.90(s，1H)，2.47(s，3H)，2.31(s，3H)，2.24(s，3H)。m/z(％)138.2(M+1，100％)。Rf(20％MeOH/EtOAc)：0.35。
Step 2:4-bromo-2,3,5-collidine-N-oxide compound
With 2,3, and 5-collidine-N-oxide compound (1.3g, 10mmol) and K 2CO 3(2.9g 20mmol) is suspended in 10mL CCl 4In.Dripping bromine (1mL, 20mmol), and with reaction mixture reflux 2h.Handle (EtOAc) and, obtain being solid title compound (1.05g, 50% productive rate) through flash chromatography (10%MeOH/EtOAc).HPLC Rt:5.24 minute. 1H-NMR(CDCl 3)：δ8.06(s，IH)，2.56，(s，3H)，2.43(s，3H)，2.31(s，3H)。m/z(％)216.2(M+1，100％)，218.2(M+3，100％)。Rf(20％MeOH/EtOAc)：0.45。
Step 3: acetic acid 4-bromo-3,5-dimethyl-pyridine-2-base methyl esters
With 4-bromo-2,3,5-collidine-N-oxide compound (0.25g 11mmol) is dissolved in the acetic anhydride (5mL), and with vlil 30 minutes.Handle and through flash chromatography (50% hexane/EtOAc), obtain title compound (0.27g, productive rate 96%).Rf (50% hexane/EtOAc): 0.70.HPLC Rt:4.76 minute. 1H-NMR(CDCl 3)：δ8.26(s，1H)，5.27(s，2H)，246(s，3H)，2.41(s，3H)，2.14(s，3H)。
Step 4:4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol
With acetic acid 4-bromo-3, and 5-dimethyl-pyridine-2-base methyl esters (0.26g, 1.0mmol) and K 2CO 3The suspension that (excessive) forms in MeOH (5mL) is heated to 50 ℃ and experience 15 minutes.Handle (CHCl 3), evaporation and filter (eluent: 100%EtOAc), obtain title compound (0.19g, productive rate 88%) into white solid by silicagel pad.Rf (50% hexane/EtOAc): 0.5.HPLC Rt:3.80 minute. 1H-NMR(CDCl 3)：δ8.23(s，1H)，4.70(s，2H)，2.46(s，3H)，2.30(s，3H)。
Step 5:4-bromo-2-brooethyl-3,5-dimethyl-pyridine
According to general step 2.4, by 4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol obtains title compound.HPLC Rt:6.32 minute. 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.63(s，2H)，2.52(s，3H)，2.40(s，3H)。
Method 2:
Step 1:2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol
As the description among the patent WO 99/10326 of Tarbit etc., by heating 2-chloromethyl-4-methoxyl group-3 in toluene, 5-dimethyl-pyridine obtains title compound.
Step 2:4-bromo-2-chloromethyl-3, the 5-lutidine
Under 130 ℃ with 2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol (8.2g, 47.8mmol) and POBr 3(60g, mixture 209mmol) stirs 3h.The toughening oil of gained is cooled in room temperature and the impouring frozen water.With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain being purple solid title compound (8.7g, productive rate 78%) its not purified just use.HPLC Rt:6.03 minute. 1H-NMR(CDCl 3)：δ8.20(s，1H)，4.62(s，2H)，2.50(s，3H)，2.38(s，3H)。
Method 3:
Figure GSA00000083249102481
Step 1:4-bromo-2-chloromethyl-3, the 5-lutidine
Under nitrogen atmosphere with PBr 32-chloromethyl-4-methoxyl group-3 in (8.0mL, 85.1mmol, 5.8 equivalents), (3.24g, 14.6mmol) suspension is heated to 80 ℃ to 5-dimethyl-pyridine.The DMF (0.50mL, 6.4mmol, 0.44 equivalent) that adds catalytic amount, during suspension become orange solution rapidly.After 40 minutes, judge reaction with HPLC and remain unfulfilled.Temperature is risen to 110 ℃ also will react prolongation 30 minutes, react completely this moment.Use NH with the mixture impouring on ice, 4OH is alkalescence and extracts with EtOAc.Wash with water, dry (salt solution, MgSO 4) and concentrate, obtain title compound (1.51g, 44%), warp into pink solid 1H-NMR determines that it contains 10% impurity.Crude product uses without just being further purified. 1H-NMR(CDC 1 3)：δ8.19(s，1H)，4.59(s，2H)，2.48(s，3H)，2.37(s，3H)。
D. The preparation of final compound
Embodiment 5.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102482
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine hydrochloride, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound (F.Seela, Liebigs Ann.Chem.1987,15).HPLC Rt:4.709 minute. 1H-NMR(CDCl 3)：δ8.23(s，1H)，6.90(m，1H)，6.38(m?1H)，5.35(s，2H)，4.99(s，2H)，3.75?(s，3H)，2.26(s，3H)，2.21(s，3H)。
Embodiment 6.7-(2-bromo-3,4,5-trimethoxy-benzyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102491
According to general step 1.3, with 2-bromo-1-chloromethyl-3,4,5-trimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.937 minute. 1H-NMR(DMSO-d 6)：δ7.11(m，1H)，6.73(s，2H)，6.42(s，1H)，6.37(m，1H)，5.23(s，2H)，3.79(s，3H)，3.75(s，3H)，3.61(s，3H)。
Embodiment 7.4-chloro-7-(2-iodo-3,4,5-trimethoxy-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102492
According to general step 1.3, with 1-chloromethyl-2-iodo-3,4,5-trimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:7.069 minute. 1H-NMR(DMSO-d 6)：δ7.08(m，1H)，6.74(s，2H)，6.38(m，1H)，6.36(s，1H)，5.19(s，2H)，3.80(s，3H)，3.77(s，3H)，3.60(s，3H)。
Embodiment 8.4-chloro-7-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102493
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine-1-oxide compound, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLCRt:5.079 minute. 1H-NMR(DMSO-d 6)：δ8.18(s，1H)，7.29(m，1H)，6.68(s，2H)，6.24(m，1H)，5.38(s，2H)，3.70(s，3H)，2.42(s，3H)，2.17(s，3H)。ESI-MS?334.2(M+1)。
Embodiment 9.4-chloro-7-(3,4,5-trimethoxy benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102501
According to general step 1.3, with 5-chloromethyl-1,2,3-trimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.036 minute. 1H-NMR(CDCl 3)：δ6.82(m，1H)，6.41(s，2H)，6.40(m，1H)，5.36(s，2H)，5.16(s，2H)，3.81(s，3H)，3.78(s，6H)。
Embodiment 10.4-chloro-7-(6-chloro-4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
According to general step 1.3, with 2-chloro-6-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.880 minute. 1H-NMR(DMSO-d 6)：δ7.06(m，1H)，6.63(s，2H)，6.32(m，1H)，5.29(s，2H)，3.74(s，3H)，2.25(s，3H)，2.21(s，3H)。
Embodiment 11.4-chloro-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102511
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.878 minute. 1H-NMR(CDC 1)：δ8.27(s，1H)，6.89(m，1H)，6.40(m，1H)，5.40(s，2H)，4.94(s，2H)，2.39(s，3H)，2.37(s，3H)。
Embodiment 12.4-chloro-7-(2-chloro-4,5-dimethoxy-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102512
According to general step 1.3, with 1-brooethyl-2-chloro-4,5-dimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.635 minute. 1H-NMR(CDC 1)：δ6.91(m，1H)，6.90(s，1H)，6.71(s，1H)，6.42(m，1H)，5.30(s，2H)，4.97(s，2H)，3.88(s，3H)，3.75(s，3H)。
Embodiment 13.7-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102513
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.072 minute. 1H-NMR(DMSO-d 6)：δ8.15(s，1H)，7.10(m，1H)，6.60(s，1H)，6.30(m，1H)，5.40(s，2H)，2.46(s，3H)，2.30(s，3H)。
Embodiment 14.4-chloro-7-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102521
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.610 minute. 1H-NMR(DMSO-d 6)：δ8.36(s，1H)，7.26(m，1H)，6.69(s，1H)，6.21(m，1H)，5.43(s，2H)，2.60(s，3H)，2.27(s，3H)。
Embodiment 15.7-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102522
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.734 minute. 1H-NMR(DMSO-d 6)：δ8.33(s，1H)，7.24(m，1H)，6.69(s，1H)，6.25(m，1H)，5.47(s，2H)，2.65(s，3H)，2.29(s，3H)。
Embodiment 16.4-chloro-7-(3,5-dimethoxy-2-nitro-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102523
According to general step 1.3, with 1-brooethyl-4,5-dimethoxy-2-nitro-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.345 minute. 1H-NMR(DMSO-d 6)：δ7.73(s，1H)，7.16(m，1H)，6.72(s，2H)，6.41(s，1H)，6.40(m，1H)，5.58(s，2H)，3.92(s，3H)，3.62(s，3H)。
Embodiment 17.4-chloro-7-(3,4-two chloro-benzyls)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102531
According to general step 1.3, with 4-brooethyl-1,2-two chloro-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:7.148 minute. 1H-NMR(DMSO-d 6)：δ7.60(m，1H)，7.59(m，1H)，7.25(q，1H)，7.12(m，1H)，6.71(s，2H)，6.37(q，1H)，5.26(s，2H)。
Embodiment 18.4-chloro-7-(3,5-dimethoxy-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102532
According to general step 1.3, with 1-chloromethyl-3,5-dimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.423 minute. 1H-NMR(DMSO-d 6)：δ7.21(m，1H)，6.69(s，2H)，6.40(m，3H)，6.34(m，1H)，5.34(s，2H)，3.68(s，6H)。
Embodiment 19.4-chloro-7-(2,5-dimethoxy-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102541
According to general step 1.3, with 2-chloromethyl-1,4-dimethoxy-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.537 minute. 1H-NMR(DMSO-d 6)：δ7.13(m，1H)，6.85(d，1H)，6.82(m，1H)，6.68(s，2H)，6.35(m，1H)，6.22(d，1H)，3.78(s，3H)，3.60(s，3H)。
Embodiment 20.4-bromo-7-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102542
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (according to F.Seela, LiebigsAnn.Chim.1987, in 15 for 4-chloro-7H-pyrrolo-[2,3-d] description of pyrimidine-2-base amine, just use POBr 3Replace POCl 3And obtain), obtain title compound.HPLC Rt:5.158 minute. 1H-NMR(DMSO-d 6)：δ8.18(s，1H)，7.29(m，1H)，6.69(s，2H)，6.15(m，1H)，5.37(s，2H)，3.70(s，3H)，2.42(s，3H)，2.17(s，3H)。
Embodiment 21.4-bromo-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102543
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.803 minute. 1H-NMR(DMSO-d 6)：δ8.20(s，1H)，7.04(m，1H)，6.61(s，2H)，6.21(m，1H)，5.38(s，2H)，2.42(s，3H)，2.28(s，3H)。
Embodiment 22.4-bromo-7-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102551
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.688 minute. 1H-NMR(DMSO-d 6)：δ8.35(s，1H)，7.25(m，1H)，6.70(s，2H)，6.15(m，1H)，5.43(s，2H)，2.60(s，3H)，2.27(s，3H)。
Embodiment 23.4-bromo-7-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102552
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.996 minute. 1H-NMR(DMSO-d 6)：δ8.15(s，1H)，7.05(m，1H)，6.61(s，2H)，6.21(m，1H)，5.43(s，2H)，2.46(s，3H)，2.30(s，3H)。
Embodiment 24.4-bromo-7-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102561
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:5.798 minute. 1H-NMR(DMSO-dX)：δ8.33(s，1H)，7.24(m，1H)，6.71(s，2H)，6.15(m，1H)，5.46(s，2H)，2.64(s，3H)，2.29(s，3H)。
Embodiment 25.4-bromo-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102562
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:4.847 minute. 1H-NMR(DMSO-d 6)：δ8.07(s，1H)，7.03(m，1H)，6.60(s，2H)，6.20(m，1H)，5.29(s，2H)，3.72(s，3H)，2.24(s，3H)，2.17(s，3H)。
Embodiment 26.4-bromo-7-(3,5-dimethoxy-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102563
According to general step 1.3, with 1-chloromethyl-3,5-dimethoxy-benzene, alkylation 4-bromo-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.490 minute. 1H-NMR(CDC)：δ7.20(m，1H)，6.70(s，2H)，6.40(s，1H)，6.34(s，2H)，6.23(m，1H)，5.16(s，2H)，3.69(s，6H)。
Embodiment 27.4-chloro-7-(3-methoxyl group-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Figure GSA00000083249102571
According to general step 1.3, with 1-chloromethyl-3-methoxyl group-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:7.177 minute. 1H-NMR(DMSO-d 6)：δ7.26-7.18(m，2H)，6.82-6.80(m，1H)，6.67(s，1H)，6.70-6.67(m，3H)，6.32-6.30(m，1H)，5.20(s，2H)，3.68(s，3H)。
Embodiment 28.4-chloro-7-(4-methoxyl group-benzyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
According to general step 1.3, with 1-chloromethyl-4-methoxyl group-benzene, alkylation 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLC Rt:6.889 minute. 1H-NMR(DMSO-d 6)：δ7.19-7.16(m，3H)，6.90-6.88(m，2H)，6.69(s，2H)，6.32-6.30(m，1H)，5.18(s，2H)，3.71(s，3H)。
Embodiment 29.N-[4-chloro-5-iodo-7-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102573
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.812 minute. 1H-NMR(DMSO-d 6)：δ10.20(s，1H)，8.13(s，1H)，7.97(s，1H)，5.50(s，2H)，3.72(s，3H)，2.50(s，3H)，2.16(s，3H)，1.22(s，9H)。
Embodiment 30.N-[7-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102581
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:7.630 minute. 1H-NMR(DMSO-d 6)：δ10.21(s，1H)，8.30(s，1H)，7.91(s，1H)，5.59(s，2H)，2.72(s，3H)，2.28(s，3H)，1.22(s，9H)。
Embodiment 31.N-[4-chloro-5-iodo-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102582
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation N-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide (A.Gangjee, J.Med.Chem.2003,46,591), obtain title compound.HPLC Rt:6.627 minute. 1H-NMR(DMSO-d 6)：δ10.15(s，1H)，8.05(s，1H)，7.73(s，1H)，5.46(s，2H)，3.74(s，3H)，2.33(s，3H)，2.16(s，3H)，1.21(s，9H)。
Embodiment 32.N-[7-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102591
According to general step 1.3, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.806 minute. 1H-NMR(DMSO-d 6)：δ10.13(s，1H)，8.30(s，1H)，7.74(m，1H)，6.52(m，1H)，5.62(s，2H)，2.73(s，3H)，2.28(s，3H)，1.23(s，9H)。
Embodiment 33.N-[4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102592
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation N-(4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.087 minute. 1H-NMR(CDC 1)：δ8.18(s，1H)，8.13(s，1H)，7.18(m，1H)，6.49(m，1H)，5.50(s，2H)，3.72(s，3H)，2.26(s，3H)，2.22(s，3H)，1.34(s，9H)。
Embodiment 34.N-[4-chloro-7-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102601
According to general step 1.3, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.115 minute. 1H-NMR(CDC 1)：δ8.12(s，1H)，8.02(s，1H)，7.93(m，1H)，6.49(m，1H)，5.71(s，2H)，3.76(s，3H)，2.70(s，3H)，2.22(s，3H)，1.36(s，9H)。
Embodiment 35.N-[4-chloro-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102602
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation N-(4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.761 minute. 1H-NMR(CDC 1)：δ8.23(s，1H)，8.11(s，1H)，7.15(m，1H)，6.50(m，1H)，5.71(s，2H)，2.43(s，3H)，2.33(s，3H)，1.35(s，9H)。
Embodiment 36.N-[4-chloro-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102603
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation N-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:7.508 minute. 1H-NMR(CDC 1)：δ8.17(s，1H)，8.11(s，1H)，8.07(s，1H)，5.77(s，2H)，2.81(s，3H)，2.33(s，3H)，1.37(s，9H)。
Embodiment 37.N-[4-chloro-7-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102611
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:6.688 minute. 1H-NMR(CDC 1)：δ8.15(s，1H)，8.09(s，1H)，7.87(m，1H)，6.47(m，1H)，5.77(s，2H)，2.84(s，3H)，2.31(s，3H)，1.37(s，9H)。
Embodiment 38.N-[4-chloro-7-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-2,2-dimethyl-propionic acid amide
Figure GSA00000083249102612
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation N-(4-chlorine 5-iodo-pyrrolo-[2,3-d] pyrimidine-2-base)-2,2-dimethyl-propionic acid amide obtains title compound.HPLC Rt:7.619 minute. 1H-NMR(CDC 1)：δ8.25(s，1H)，8.13(s，1H)，7.33(s，1H)，5.55(s，2H)，2.47(s，3H)，2.36(s，3H)，1.36(s，9H)。
Embodiment 39.4-chloro-5-[(dibenzyl amino)-methyl]-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102621
Step 1. sad 4-chloro-5-[(dibenzyl amino)-methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base-acid amides
With sad the 5-[(dibenzyl amino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base }-acid amides (1.0g, 2mmol; J.Chem.Soc.Perkin Trans.11998,1637), BnNEt 3Cl (1.4g, 4mmol), PhNMe 2(0.5mL) and POC 1(1.73mL is 12mmol) at CH 3The solution that forms among the CN (9.2mL) is heated to 100 ℃, heats also to concentrate in 40 minutes.With in the residuum impouring frozen water and,, obtain title compound (0.80g, 76%) with EtOAc (50mL * 3) extraction and evaporation with 2N NaOH neutralization.HPLC?Rt：6.868min。 1H-NMR(DMSO-d 6)：δ12.19(s，1H)，10.49(s，1H)，1.45-7.21(m，11H)，3.80(s，2H)，3.59(s，4H)，2.41(t，2H)，1,56(m，2H)，1.27(br?s?8H)，0.85(t，3H)。
Step 2.4-chloro-5-[(dibenzyl amino)-methyl]-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
With sad 4-chloro-5-[(dibenzyl amino)-methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base-acid amides (150mg, 0.30mmol), 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine (56mg, 0.30mmol) and K 2CO 3(84mg, 0.60mmol) suspension that forms in dry DMF (1mL) is heated to 45 ℃ and spend the night.After treated (EtOAc) and the evaporation, residuum is absorbed among the 4N HCl (1mL) of methyl alcohol, at room temperature stirring 1h and being neutralized to pH with the NaOH of 2N is 7.With EtOAc (10mL * 3) extraction, evaporation and by preparation property TLC (MeOH/CH 2Cl 210: 1) purifying, obtain title compound (70.5mg, 45%).HPLC?Rt：5.362min。 1H-NMR(DMSO-d 6)：δ8.05(s，1H)，7.30-7.22(m，10H)，6.99(s，1H)，6.57(s，2H)，5.27(s?2H)，3.70(s，2H)，3.65(s，3H)，3.54(s，4H)，2.17(s，3H)，2.15(s，3H)。
Embodiment 40.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-phenyl amino methyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102631
Sad (4-chloro-5-phenyl amino methyl-7H-pyrrolo-[2,3-d] the pyrimidine-2-base)-acid amides of step 1.
The sealing test tube in sad the 5-[(dibenzyl amino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base }-acid amides (2.42g, 3mmol) and the solution of aniline (10mL) be heated to 90 ℃ and the experience whole night, concentrate, filter and wash with MeOH (2mL * 3), obtain title compound (1.1g, 57%).HPLC?Rt：6.327min。 1H-NMR(DMSO-d 6)：δ11.77(s，1H)，11.47(s，1H)，11.37(s，1H)，7.05(m，2H)，6.85(s，1H)，6.62(m，2H)，6.52(m，1H)，5.58(t，1H)，4.31(d，2H)，2.43(t，2H)，1.58(m，2H)，1.27(m，8H)，0.86(t，3H)。
Step 2.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-phenyl amino methyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
With sad (4-chloro-5-phenyl amino methyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides (270mg, 0.68mmol), BnNEt 3Cl (0.48g, 1.36mmol), PhNMe 2(0.17mL) and POC 1(0.59mL is 4.08mmol) at CH 3The solution that forms among the CN (3mL) is heated to 100 ℃, heats also to concentrate in 40 minutes.To neutralize in the residuum impouring frozen water and with 2N NaOH, with EtOAc (20mL * 3) extraction, evaporation obtains being 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine (282mg) oily crude product, its not purified just use.With this crude product (282mg, 0.68mmol), 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine (140mg, 0.68mmol) and Cs 2CO 3(266mg, 0.68mmol) suspension that forms in dry DMF (1mL) is heated to 45 ℃ and spend the night.After treated (EtOAc) and the evaporation, residuum is absorbed among the 4N HCl (1mL) of methyl alcohol, at room temperature stirring 1h and being neutralized to pH with the NaOH of 2N is 7.With EtOAc (10mL * 3) extraction, evaporation and by preparation property TLC (MeOH/CH 2C 110: 1) purifying, obtain title compound (4.8mg, 1.6%).HPLC?Rt：4.785min。 1H-NMR(DMSO-d 6)：δ8.12(s，1H)，7.18(m，2H)，6.75(m，2H)，6.60(s，1H)，5.26(s，2H)，4.93(s?2H)，4.74(s，2H)，3.70(s，3H)，3.00(s，3H)，2.23(s，3H)，2.16(s，3H)。
Embodiment 41.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102641
Step 1. sad (4-chloro-5-[(methyl-phenyl-amino) methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides
As the step 1 of embodiment before, sad by handling the 5-[(dibenzyl amino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base }-acid amides (2.42g, 3mmol) and methylphenylamine (10mL) and obtain title compound.HPLC?Rt：6.325min。 1H-NMR(DMSO-d 6)：δ11.73(s，1H)，11.47(s，1H)，11.35(s，1H)，7.13(m，2H)，?6.78(s，2H)，6.60(m，2H)，4.64(s，2H)，2.98(s，3H)，2.43(t，2H)，1.58(m，2H)，1.27(m，8H)，0.86(t，3H)。
Step 2.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-[(methyl-phenyl-amino) methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
As the step 2 of embodiment before, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-5-[(methyl-phenyl-amino) methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base }-acid amides, and, obtain title compound with 4N HCl deprotection.HPLC?Rt：4.844min。 1H-NMR(DMSO-d 6)：δ8.20(s，1H)，7.16(m，2H)，6.87(s，1H)，6.70-6.64(m，2H)，5.28(s，2H)，5.13(s?2H)，4.46(s，2H)，4.15(br?s，1H)，3.73(s，3H)，2.25(s，3H)，2.18(s，3H)。
Embodiment 42.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102651
Sad (4-chloro-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides of step 1.
With sad (4-oxo-6-tetramethyleneimine-1-ylmethyl-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides (0.36g, 1mmol; J.Chem.Soc.Perkin Trans.11998,1637), BnNEt 3Cl (0.70g, 2mmol), PhNMe 2(0.25mL) and POC 1(0.86mL is 6mmol) at CH 3The solution that forms among the CN (5mL) is heated to 100 ℃, keeps 40 minutes, and concentrates.To neutralize in the residuum impouring frozen water and with 2N NaOH, with EtOAc (50mL * 3) extraction and evaporation, obtain sad (4-chloro-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides (0.33g), its not purified just use for crude product.HPLC?Rt：6.737min。 1H-NMR(DMSO-d 6)：δ11.60(br?s，1H)，10.20(br?s，1H)，6.38(s，1H)，3.86(s，2H)，2.90(m，2H)，2.70(9s，4H)，1.86(s，4H)，1.78(t，2H)，?1.32-1.29(m，8H)，0.90(t，3H)。
Step 2.4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
With thick sad (4-chloro-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base)-acid amides (330mg, 0.87mmol), 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine (162mg, 0.87mmol) and K 2CO 3(121mg, 0.87mmol) suspension that forms in dry DMF (1mL) is heated to 45 ℃ and spend the night.After treated (EtOAc) and the evaporation, residuum is absorbed among the methyl alcohol HCl (1mL) of 6N of methyl alcohol, at room temperature stirring 1h and being neutralized to pH with 2NNaOH is 7.With EtOAc (10mL * 3) extraction, evaporation and by preparation property TLC (MeOH/CH 2C 110: 1) purifying, obtain 4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-6-tetramethyleneimine-1-ylmethyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (4.1mg, productive rate 1.0%).HPLC?Rt：6.092min。 1H-NMR(DMSO-d 6)：δ8.09(s，1H)，6.31(s，1H)，5.55(s，2H)，4.85(s，2H)，3.77(s，3H)，3.52(brs，2H)，2.43(m，4H)，1.76-1.71(m，4H)。
Embodiment 43.4-chloro-5-sec.-propyl-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102661
Step 1.3-bromo-4-methyl-valeral
25 ℃ stir down 4-methyl-valeral (8.60g, 0.10mol), 5,5-dibromo barbituric acid (DBBA, 17.15g, 0.06mol), 40%HBr (2mL) and HOAc (1mL) be at CH 2C 1The mixture 5h that forms (180mL).After the filtration, use 1N Na 2SO 3, Na 2CO 3With salt water washing filtrate, use Na 2SO 4Dry also evaporation obtains 3-bromo-4-methyl-valeral (8.76g, 53%). 1H-NMR(CDC 1)：δ9.40(s，1H)，4.40(t，1H)，2.10(m，1H)，1.06(s，3H)，1.05(s，3H)。
Step 2.2-amino-5-sec.-propyl-3,7-dihydro-pyrrolo-[2,3-d] pyrimidin-4-one
Under 25 ℃ with 4-diamino-6-hydroxy pyrimidine (6.68g, 50mmol), (8.3g, 100mmol) (8.76g is 50mmol) at CH with 3-bromo-4-methyl-valeral for AcONa 3CN (100mL) and H 2The suspension that forms among the O (100mL) stirs and spends the night, during raw material dissolve gradually, and be settled out pyrrolo-[2, the 3-d] pyrimidine of hope.Filter the collecting precipitation thing and, obtain 2-amino-5-sec.-propyl-3,7-dihydro-pyrrolo-[2,3-d] pyrimidin-4-one (3.80g, 40%) with the MeOH washing.HPLC?Rt：4.408min。 1H-NMR(DMSO-d 6)：δ10.58(s，1H)，10.10(s，1H)，6.30(s，1H)，5.97(s，2H)，3.03(7，1H)，1.20(s，3H)，1.19(s，3H)。
Step 3.4-chloro-5-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Reflux and heat 2-amino-5-sec.-propyl-3 down, the mixture 3h of 7-dihydro-pyrrolo-[2,3-d] pyrimidin-4-one and acetic anhydride (20mL) and evaporation.Use CH under 100 ℃ 3BnNEt among the CN (100mL) 3Cl (8.99g, 40mmol), PhNMe 2(4.9mL) and POC 1(17mL 120mmol) handles residuum and also concentrated in 40 minutes.To in the residuum impouring frozen water and use 2N NaOH neutralization, and obtain oily matter with EtOAc (80mL * 3) extraction and evaporation, it is at 50 ℃ of 4N HCl (50mL) boiling 2h that use methyl alcohol down.After the cooling, being neutralized to pH with 2N NaOH is 7, and solid collected by filtration is also dry, obtains 4-chloro-5-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (1.88g, 45%).HPLC?Rt：5.796min。 1H-NMR(DMSO-d 6)：δ11.170(s，1H)，6.82(s，1H)，6.42(s，2H)，3.24(7，1H)，1.25(s，3H)，1.23(s，3H)。
Step 4.4-chloro-5-sec.-propyl-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
With 4-chloro-5-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (105mg, 0.5 mmol), 2-chloromethyl-4-methoxyl group-3, and 5-dimethyl-pyridine (93mg, 0.5mmol) and K 2CO 3(85mg, 0.6mmol) suspension that forms in dry DMF (1mL) is heated to 45 ℃ and heating whole night.Handle (EtOAc), evaporation and with preparation property TLC (MeOH/CH 2C 110: 1) purifying, obtain 4-chloro-5-sec.-propyl-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (36mg).HPLC?Rt：5.867min。 1H-NMR(DMSO-d 6)：δ8.07(s，1H)，6.74(s，1H)，6.51(s，2H)，5.22(s，2H)，3.70(s，3H)，3.23(7，1H)，2.21(s，3H)，2.15(s，3H)。
Embodiment 44.4-chloro-7-(4-methoxyl group-3-methyl-pyridine-2-ylmethyl)-5-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
According to general step 1.3, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-5-isobutyl--7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLCRt：6.997min。 1H-NMR(CDC 1)：δ8.27(s，1H)，6.61(s，1H)，5.33(s，2H)，5.09(s，2H)，3.35(7，1H)，2.35(s，6H)，1.25(s，3H)，1.23(s，3H)。
Embodiment 45.4-chloro-7-(4-chloro-3-methyl isophthalic acid-oxygen-pyridine-2-ylmethyl)-5-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102682
According to general step 1.3, with 2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-5-isobutyl--7H-pyrrolo-[2,3-d] pyrimidine-2-base amine obtains title compound.HPLCRt：6.753min。 1H-NMR(DMSO-d 6)：δ8.37(s，1H)，7.03(s，1H)，6.63(s，?2H)，5.40(s，2H)，3.20(7，1H)，2.59(s，3H)，2.27(s，3H)，1.20(s，3H)，1.19(s，3H)。
Embodiment 46.4-chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base-amine
Figure GSA00000083249102691
Step 1.4-(tertiary butyl-phenylbenzene-silanyloxy base)-Ding-1-alcohol
Stir tBuPh under the room temperature 2SiCl (25mL, 98mmol), 1, the 4-butyleneglycol (25mL, 281mmol), iPrNEt 2(50mL, 303mmol) and CH 2C 1Mixture 14h (50mL) concentrates, with ether dilution, water (3 *) and salt water washing.Dry (Na 2SO 4) and concentrate, obtaining title compound (29.8g, 93%) into edible vegetable oil, it uses without just being further purified.Rf (EtOAc: hexane 1: 4) 0.3. 1H-NMR(CDC 1)：δ7.71(dd，4H)，7.43(m，6H)，3.74(t，2H)，3.70(q，2H)，2.10(br.t，1H)，1.69(m，4H)，1.08(s，9H)。
Step 2.4-(tertiary butyl-phenylbenzene-silanyloxy base)-butyraldehyde
With 4-(tertiary butyl-phenylbenzene-silanyloxy base)-(29.8g is 91mmol) at CH for Ding-1-alcohol 2C 1(70 mL) solution in join PCC (21.5g, 100mmol), diatomite (50g) and CH 2C 1In the slurry (300mL).The 2h that stirs the mixture under the room temperature removes by filter diatomite and uses CH 2C 1300mL) washing.Concentrate and, obtain title compound (22.2g, 75%) into edible vegetable oil through chromatogram (EtOAc/ hexane 4: 1).Rf (EtOAc: hexane 1: 4) 0.7. 1H-NMR(CDC 1)：δ9.82(t，1H)，7.68(dd，4H)，7.41(m，6H)，3.71(t，2H)，2.57(t，2H)，1.91(q，2H)，1.07(s，9H)。
Step 3.2-bromo-4-(tertiary butyl-phenylbenzene-silanyloxy base)-butyraldehyde
The HBr aqueous solution with 70% (1mL, 14mmol) handle 4-(tertiary butyl-phenylbenzene-silanyloxy base)-butyraldehyde (22.2g, 68mmol), 5,5-dibromo barbituric acid (12.1g, 43mmol) and CH 2C 1Mixture (80mL), and at room temperature stir 1h.Remove by filter by product (barbituric acid) and use CH 2C 1(100mL) washing.The organic layer that is combined washs (1N Na 2S 2O 3, 5%NaHCO 3, half saturated brine) and dry (Na 2SO 4).Concentrate the title compound (25.3g, 92%) that obtains to edible vegetable oil, it uses without just being further purified.Rf (EtOAc: hexane 1: 4) 0.7. 1H-NMR(CDC 1)：δ9.55(d，1H)，7.68(dd，4H)，7.41(m，6H)，4.60(ddd，1H)，3.84(m，2H)，2.35(m，1H)，2.10(m，1H)，1.07(s，9H)。
Step 4.2-amino-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-3,7-dihydro-pyrrolo-[2,3-d] pyrimidin-4-one
According to general step 1.1, with 2, (10.2g, (25.3g 62mmol), obtains title compound (23.4g, 87%) to 4-diamino-6-hydroxy pyrimidine 124mmol) to handle 2-bromo-4-(tertiary butyl-phenylbenzene-silanyloxy base)-butyraldehyde.HPLC?Rt：6.981min。 1H-NMR(CDCl)：δ10.67(s，1H)，10.14(s，1H)，7.55(m，4H)，7.38(m，6H)，6.37(s，1H)，5.98(s，2H)，3.86(t，2H)，2.86(t，2H)，0.95(s，9H)。
Step 5.N-{7-ethanoyl-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base }-ethanamide
With 2-amino-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-3, (22.7g is 52mmol) at Ac for 7-dihydro-pyrrolo-[2,3-d] pyrimidin-4-one 2Solution among the O (200mL) is heated to 110 ℃, and heating 2.5h, concentrates, also concentrates once more with toluene (300mL) dilution, obtains the title compound crude product (27g) into brown oil, and it uses without just being further purified.In order to have characterized with chromatogram purification an aliquots containig.HPLC?Rt：8.349min。 1H-NMR(CDCl)：δ11.77(s，1H)，8.81(s，1H)，7.61(dd，4H)，7.30(m，7H)，6.37(s，1H)，4.00(t，2H)，3.02(t，2H)，2.70(s，3H)，2.23(s，3H)，1.04(s，9H)。
Step 6.N-{7-ethanoyl-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base }-ethanamide
Thick N-{7-ethanoyl-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-oxo-4,7-dihydro-3H-pyrrolo-[2,3-d] pyrimidine-2-base }-ethanamide (26.4g, 51mmol), BnNEt 3Cl (23.2g, 102mmol), PhNMe 2(19.6mL, 153mmol) and POCl 3(9.3mL is 77mmol) at CH 3The solution that forms among the CN (100mL) is heated to 80 ℃ and heat 1.5h.With EtOAc (800mL) diluted mixture thing, washing (saturated NaHCO 3, salt solution) and concentrate, obtain title compound (46g) into oil, it uses without just being further purified.In order to have characterized with chromatogram purification an aliquots containig.HPLC?Rt：8.562min。 1H-NMR(CDCl 3)：δ8.05(s，1H)，7.68(s，1H)，7.57(dd，4H)，7.40(m，6H)，3.99(t，2H)，3.06(t，2H)，2.98(s，3H)，2.52(s，3H)，1.04(s，9H)。
Step 7.N-{5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base }-ethanamide
Use K under the room temperature 2CO 3(8.0g 58mmol) handles thick N-{7-ethanoyl-5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base }-solution of ethanamide (46g) in MeOH (150mL) 15 minutes.Filter, concentrate and process chromatogram (EtOAc/ hexane 1: 1), obtain inscribing compound, it is by the remaining PhNMe of step 6 2The oil that pollutes.Handle with EtOAc (40mL) the described oil of dilution and with hexane (40mL), obtain product (4.2g, 3 steps are 16%) into faint yellow sedimentary hope.HPLC?Rt：8.558min。 1H-NMR(CDCl 3)：δ11.75(br.s，1H)，11.35(br.s，1H)，7.60(dd，4H)，7.37(m，6H)，3.97(t，2H)，3.10(t，2H)，2.57(s，3H)，1.06(s，9H)。
Step 8.N-[5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-ethanamide
Under the room temperature with N-{5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-2-base }-ethanamide (344mg, 0.70mmol), 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine hydrochloride (175mg, 0.77mmol), K 2CO 3(516mg, 3.7mmol) and the mixture of DMF (3.0mL) stir and to spend the night.Treated (EtOAc/ water, salt solution) obtains being off-white solid title compound, and it just uses (516mg, " 115% ") without being further purified.HPLC?Rt：8.419min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，δ7.95(s，1H)，7.55(dd，4H)，7.32(m，6H)，7.04(s，1H)，5.37(s，2H)，3.91(t，2H)，3.73(s，3H)，3.06(t，2H)，2.57(s，3H)，2.26(s，3H)，2.25(s，3H)，0.97(s，9H)。
Step 9.5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Handle N-[5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl with NaOH 2M (3mL) down for 45 ℃]-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base]-the solution 1.5h of ethanamide (511mg) in THF (3mL) and MeOH (3mL).Treated and process chromatogram (EtOAc/ hexane 1: 1) obtains the title compound (290mg, 2 steps are 69%) into white powder.HPLC?Rt：8.198min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，7.57(dd，4H)，7.40(m，2H)，7.32(m，4H)，6.69(s，1H)，5.26(s，2H)，4.90(s，2H)，3.98(t，2H)，3.66(s，3H)，3.00(t，2H)，2.24(s，3H)，2.18(s，3H)，0.96(s，9H)。
Step 10.2-[2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-ethanol
Use TBAF (the 1N solution among the THF under the room temperature, 0.5mL, 0.50mmol) processing 5-[2-(tertiary butyl-phenylbenzene-silanyloxy base)-ethyl]-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine (246mg, 0.41mmol) the solution 1h in THF (5mL).Treated (EtOAc/ water, salt solution) obtains the crude product into oil, and (15mL) dilutes it with ether, during the product of wishing from solution, be precipitated out, it is white powder (110mg, 74%).HPLC?Rt：4.474min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，6.78(s，1H)，5.30(s，2H)，4.93(s，2H)，3.87(t，2H)，3.76(s，3H)，3.03(t，2H)，2.26(s，3H)，2.23(s，3H)。
Step 11. methylsulfonic acid 2-[2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-ethyl ester
Under the room temperature with MsCl (11 μ L are 0.14mmol) to 2-[2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-ethanol (11.6mg, 0.031mmol) and Et 3N (30 μ L, 0.22mmol) solution in THF (2mL) carries out 15 minutes processing, obtains the solution of title compound, and it uses without just being further purified.In independent experiment, with the described material of preparation property TLC (EtOAc 100%) purifying.HPLC?Rt：4.765min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，6.80(s，1H)，5.31(s，2H)，4.93(s，2H)，4.42(t，2H)，3.77(s，3H)，2.98(t，2H)，2.85(s，3H)，2.23(s，3H)，2.07(s，3H)。
Step 12.4-chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2,3-d] pyrimidine-2-base amine
Use i-BuNH 2(4mL) be diluted in methylsulfonic acid 2-[2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-7H-pyrrolo-[2, the 3-d] pyrimidine-5-yl that obtains in the step 11]-solution of ethyl ester in THF, and under 50 ℃, heat 15h.Concentrate, handle (the saturated NaHCO of EtOAc/ 3Salt solution) also through preparation property TLC (MeOH: Et 3N: CH 2Cl 27: 3: 100), obtain title compound (6mg, 50%) into water white oil.HPLC?Rt：4.263min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，6.79(s，1H)，5.29(s，2H)，4.97(s，2H)，3.76(s，3H)，3.04(t，2H)，2.96(t，2H)，2.53(d，2H)，2.26(s，3H)，2.22(s，3H)，1.85(oct.，1H)，0.90(d，6H)。
Embodiment 47.2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102731
According to general step 1.2, obtain title compound by the condensation between (2-amino-4,6-two chloro-pyrimidine-5-yl)-vinyl acetic monomer and C-(4-methoxyl group-3,5-dimethyl-pyridine-2-the yl)-methylamine.HPLC?Rt：4.893min。 1H-NMR(CDCl 3)：δ8.07(s，1H)，5.03(s，2H)，4.92(s，2H)，3.77(s，3H)，3.57(s，2H)，2.31(s，3H)，2.20(s，3H)。
Embodiment 48.2-amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102741
According to general step 1.3, with 2-chloromethyl-4-chloro-3,5-dimethyl-pyridine, alkylation 4-chloro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：5.367min。 1H-NMR(CDCl 3)：δ8.09(s，1H)，5.02(s，2H)，4.96(s，2H)，3.57(s，2H)，2.45(s，3H)，2.29(s，3H)。
Embodiment 49.2-amino-4-chloro-7-(3,5-dimethyl-4-methoxyl group-1-oxygen-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102742
According to general step 2.1, with m-CPBA oxidation 2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：4.763min。 1H-NMR(DMSO-d 6)：δ8.01(s，1H)，7.01(s，2H)，4.93(s，2H)，3.73(s，3H)，3.46(s，2H)，2.40(s，3H)，2.19(s，3H)。
Embodiment 50.2-amino-4-chloro-7-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102743
According to general step 2.1, with m-CPBA oxidation 2-amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：4.90min。 1H-NMR(CDCl 3/CD 3OD)：δ7.96(s，1H)，5.12(s，2H)，3.38(s，2H)，2.47(s，3H)，2.27(s，3H)。
Embodiment 51.2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
According to general step 1.2, by (2-amino-4,6-two chloro-pyrimidine-5-yl)-vinyl acetic monomer and 3,4, the condensation between 5-trimethoxy-benzyl amine obtains title compound.HPLC?Rt：6.391min。 1H-NMR(CDCl 3)：δ6.70(s，2H)，5.14(s，2H)，4.77(s，2H)，3.84(s，6H)，3.81(s，3H)，3.47(s，2H)。
Embodiment 52.2-amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102752
According to general step 3.1, handle 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5 with the bromine in the acetic acid, 7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：7.150min。 1H-NMR(CDCl 3)：δ6.49(s，1H)，5.14(s，2H)，4.94(s，2H)，3.90(s，3H)，3.86(s，3H)，3.75(s，3H)，3.55(s，2H)。
Embodiment 53.2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5-methyl-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102753
According to general step 1.5, use methyl iodide, alkylation 2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：4.091min。 1H-NMR(CDCl 3)：δ8.01(s，1H)，5.15(s，2H)，4.93(d，1H)，4.87(d，1H)，3.76(s，3H)，3.51(s，1H)，2.29(s，3H)，2.20(s，3H)，1.78(s，3H)。
Embodiment 54.2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,5-dimethyl-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102761
According to general step 1.5, use methyl iodide, alkylation 2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：5.002min。 1H-NMR(CDCl 3)：δ8.02(s，1H)，5.02(s，2H)，4.90(s，2H)，3.75(s，3H)，2.29(s，3H)，2.18(s，3H)，1.53(s，6H)。
Embodiment 55.2-amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzyl)-5,5-dimethyl-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102762
According to general step 1.5, use methyl iodide, alkylation 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：6.944min。 1H-NMR(CDCl 3)：δ6.34(s，1H)，5.09(s，2H)，4.93(s，2H)，3.90(s，3H)，3.86(s，3H)，3.71(s，3H)，1.52(s，6H)。
Embodiment 56.4-chloro-5-hydroxyl-2-imino--7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-2,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
According to general step 1.6, with tin anhydride oxidation 2-amino-4-chloro-7-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：4.294min。 1H-NMR(CDCl 3)：δ8.04(s，1H)，5.93(s，1H)，5.76(s，1H)，4.97(s，2H)，3.765(s，3H)，2.29(s，3H)，2.20(s，3H)。
Embodiment 57.4-chloro-5-hydroxyl-2-imino--7-(3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102772
According to general step 1.6, with tin anhydride oxidation 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：6.156min。 1H-NMR(CDCl 3)：δ6.68(s，2H)，6.12(s，1H)，5.93(s，1H)，4.84(s，2H)，3.86(s，6H)，3.83(s，3H)。
Embodiment 58.4-chloro-5-hydroxyl-2-imino--7-(2-bromo-3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone
Figure GSA00000083249102773
According to general step 1.6, by oxidation 4-chloro-5-hydroxyl-2-imino--7-(2-bromo-3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo-[2,3-d] pyrimidine-6-ketone obtains title compound.HPLC?Rt：6.230min。 1H-NMR(CDCl 3)：δ6.57(s，1H)，6.14(s，1H)，5.91(s，1H)，5.01(s，2H)，3.90(s，3H)，3.87(s，3H)，3.78.(s，3H)。
Biology embodiment
Embodiment A .rHSP90 CBA
By cultivating a night down at 4 ℃, (Canada #SPP-770) is coated on 96 orifice plates for Stressgen, BC with the pure rHSP90 protein of 5 micrograms in the phosphated buffer saline (PBS).Remove unconjugated protein and with the hole of 200 μ L PBS washing coating 2 times.Add DMSO contrast (thinking untreated sample) or test compound with 100-30-10-3-1-0.3 μ M extent of dilution (in PBS) then, on the orifice plate vibratory screening apparatus, mixed orifice plate 30 seconds, cultivated 60 minutes down at 37 ℃ then.With 200 μ L PBS washing holes 2 times, add 10 μ M biotinylation-geldanamycin (vitamin H-GM) and at 37 ℃ cultivated 60 minutes down.Use 200 μ L PBS washing holes 2 times once more, (streptavidin-PE) (molecular probe, Eugene OR) and at 37 ℃ cultivated 60 minutes down to add 20 μ g/mL streptavidin-phycoerythrin then.With 200 μ L PBS washing hole 2 times again.Use have at the 485nm place SpectraMax Gemini XS spectrofluorometer that excites and have emission at the 580nm place (molecular device, Sunnyvale CA) measure relative fluorescence unit (RFU); Use SOFTmax
Figure GSA00000083249102781
(Molecular Devices Corporation, Sunnyvale CA) obtain data to PRO software.Background definition is: do not apply the RFU that the hole produced that HSP90 still handles with vitamin H-GM and streptavidin-PE.Before other calculates, subtracting background from each sample of being handled by vitamin H-GM and streptavidin-PE.Calculating of each sample in conjunction with suppressing the value of percentage after by subtracting background, as follows:
% is in conjunction with inhibiting rate=[RFU that untreated RFU-is treated]/[untreated RFU] * 100.
Embodiment B. cell lysate is in conjunction with test
By (20mM HEPES, pH 7.3,1mM EDTA, 5mMMgCl at molten born of the same parents' damping fluid 2, 100mM KCl) in carry out homogenize (douncing) and prepare MCF7 breast cancer cell lysate, then under 4 ℃, cultivated 30 minutes being with or without under the situation of test compound, afterwards at 4 ℃ down with being connected in BioMag TMThe vitamin H of streptavidin magnetic beads (Qiagen)-GM cultivated 1 hour.Be placed on test tube on the Magnetic rack and remove the unconjugated upper strata stillness of night.The washing magnetic beads is 3 times in molten born of the same parents' damping fluid, and boils under 95 ℃ 5 minutes in SDS-PAGE sample damping fluid.Analytical sample on the SDS protein adhesive carries out the Western marking with regard to rHSP90.Use Bio-rad Fluor-S uses the band among the imager quantitative assay Western Blot more, calculates the bonded % inhibiting rate of rHSP90 to vitamin H-GM.
In the table 5 based on above-mentioned experimental summary the lysate binding ability of selected The compounds of this invention.The IC of report 50For in the MCF7 cell lysate, the concentration of required test compound when the inhibition that is bonded to rHSP90 for vitamin H-GM reaches 50% inhibiting rate.
The Embodiment C .HER2 test of degrading
Growth MCF7 breast cancer cell (ATCC) in the Eagle ' s medium (DMEM) of the Dulbecco ' s modification that contains 10% fetal bovine serum (FBS) and 10mM HEPES, and be placed on 24 orifice plates (50% merges).After 24 hours (cytogamy 65-70%), add test compound and through incubated overnight 16 hours.For the relatively poor compound of validity, add-on is 100 μ M, 10 μ M and 1 μ M, and for validity compound preferably, add-on is 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M, 0.01 μ M and 0.03 μ M.Add 200 μ L trypsinase with salt solution (PBS) washing hole of 1mL phosphate buffered and in each hole.After trypsin acting finishes, in each hole, add 50 μ L FBS.Then with 200 μ L cell transfer in 96 orifice plates.Draw cell back and forth to obtain single cell suspending liquid with pipette.Use Sorvall Legend RT TMThe desktop whizzer (Kendro Laboratory Products, Asheville, NC) 2, under the 500rpm with centrifugal 1 minute of orifice plate.Washed cell in the PBS that contains 0.2%BSA and 0.2% sodiumazide (BA damping fluid) then.Extent of dilution according to 1: 20 and 1: 40 (final concn is 1 μ g/mL), add anti-HER2/Neu antibody (the Becton Dickinson of phycoerythrin (PE) link coupled respectively, #340552), or the PE link coupled resists-key hole relative (key-hole limpet) protometrocyte [KLH] (Becton Dickinson, #340761) control antibodies is drawn cell back and forth to form single cell suspending liquid and to cultivate 15 minutes.With 200 μ L BA damping fluid washed cells 2 times, and be suspended in again in the 200 μ L BA damping fluids, it be transferred in the FACSCAN test tube with 250 extra μ L BA damping fluids.The FACSCalibur of argon-ion laser has been assembled in use TMFlow cytometer (BectonDickinson, San Jose, CA) analytical sample, the light of wherein said laser apparatus emission 15mW, 488 nm is used to excite the PE fluorochrome.10,000 phenomenons of each sample collection.Generate the fluorescence histogram, and used Cellquest software to determine the average fluorescent strength (MFI) of each sample.Background definition is for contrasting the MFI that cell produced that IgG-PE turns out, and from each sample that is polluted by HER2/Neu antibody subtracting background.Because compound is suspended among the DMSO again, therefore use the DMSO cultured cells always as untreated contrast.The degraded percentage of HER2 calculates in the following manner:
%HER2 degraded=[MFI of (MFI of the cell that the MFI-of untreated cell is processed)/untreated cell] * 100
In the table 5 based on above-mentioned experimental summary the HER2 degradation capability of selected The compounds of this invention.IC 50Concentration when being defined as 50% degraded of HER2/Neu protein.
Embodiment D:MTS test
The cytotoxicity of MTS test determination geldanamycin derivant.(3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium is a tetrazolium dye to MTS, and it is by the desaturase of metabolic activity cell and be converted into first
Figure GSA00000083249102801
Product (Corey, A. etc., " Use of an aqueous solubletetrazolium/formazan assay for cell growthassays in culture ", and Cancer Commun.1991,3,207-212).With the quantity of 2000 cells/well with cell seeding on 96 orifice plates, and make it whole night in the Eagle ' s medium attached to the Dulbecco ' s modification that is supplemented with 10% fetal bovine serum.Final volume of culture is 100 μ L.Use Celltiter 96AQ UeousThe quantity of survivaling cell is determined in the hyperplasia test (Promega, Madison WI) of non--radioactivity.With 20: 1 mixed MTS/PMS (azophenlyene metilsulfate) solution, and join in the developing medium of 100 μ L with the amount of every hole 20 μ L.After 2-4 hour, use the porous plate spectrophotometer to measure first in 490nm absorption place
Figure GSA00000083249102802
The formation of product.By not having under the situation of cell the Abs 490nm and the MTS-PMS that measure cell culture medium determine background, and from all values subtracting background.Calculating survivaling cell percentage in the following manner:
% survivaling cell=(processed cell is at the Abs of the Abs/ at 490nm place untreated cell at the 490nm place) * 100
Summed up in the table 5 according to the effect of the selected compounds of the present invention of MTS test for the MCF7 breast cancer cell.IC is defined as the compound concentration when producing 50% survivaling cell.
The biological activity of table 5. pyrrolopyrimidine (formula I)
Figure GSA00000083249102811
Figure GSA00000083249102831
Figure GSA00000083249102841
ND does not determine.
II. The preparation of aminopurine and related compound (formula II compound)
A. Material and method
Be used to generate the chemical reagent of following new product of the present invention all commercially available from, Aldrich Chemical Co. for example, Milwaukee, WI, the U.S..Otherwise then it prepares easily and is known for those of ordinary skills, and perhaps it has mentioned in this article and describes.
Final compound adopts preparation property TLC (silica gel usually
Figure GSA00000083249102842
Whatman PartisilPK6F) or flash chromatography (silica gel
Figure GSA00000083249102843
The EMD chemical), use EtOAc/ hexane or MeOH/CH 2Cl 2Come purifying as eluent.Use silica gel tlc plate (silica gel
Figure GSA00000083249102851
The EMD chemical) measures the Rf value.Use C18 post (Agilent Zorbax 300SB-C18; 5 microns; 4.6mm * 150mm) obtain analytical HPLC chromatogram.Used constant flow rate 1mL/ minute, the ratio of A is increased to 100% (t=7.00 minute) by 5% (t=0) linearity, thereby at solvent orange 2 A (0.1%TFA in the water) and solvent B (CH 30.5%TFA among the CN) applies gradient between.Usually at MeOH or CH 3Among the CN sample is diluted to 0.1-1mg/mL, and volume injected is generally 10 μ L.Coupled columns does not heat, and carries out UV at the 254nm place and detects.Record on Bruker Avance 400MHz spectrograph 1The H-NMR spectrogram.
Use Beilstein Autonom 2.1 softwares to generate chemical name.
B. General step
1. The general step of conversion purine skeleton
General step 1.1: the alkylation on purine N-9 position
With purine (3mmol), (mixing) aryl-CH 2-halogenide (3mmol, it can add in batches if desired) and K 2CO 3(3.3mmol) suspension that forms in dry DMF (15mL) is heated to 40-60 ℃ and heat 3-10h.Handle (EtOAc) and pass through preparation property TLC or flash chromatography (EtOAc/ hexane or MeOH/CH 2Cl 2) purifying, obtain the alkylate of pure purine N-9 position.
General step 1.2: the halogenation on purine C-8 position
(r.t.) uses Br under the room temperature 2(1.3 equivalents, CHCl 3In 1M solution) handle MeOH/THF/ acetic ester damping fluid (in each AcOH and AcONa, being 1N) 16h.Evaporation, processing (EtOAc), dry (MgSO 4) and through flash chromatography, the 8-bromine purine that obtains wishing.
General step 1.3: the nucleophilic substitution on purine C-6 position
Detailed description is referring to J.Med.Chem.1999, and 42,2064-2086.
A) sulfanyl derivatives: the suspension reflux that 6-chloropurine and sodium mercaptides or potassium are formed in THF 6-24 hour.Handle (EtOAc) and process flash chromatography, the 6-sulfane base purine that obtains wishing.
B) alkoxy derivative: the suspension reflux that 6-chloropurine and alkoxide are formed in suitable alcohol 1-16 hour, water cancellation afterwards.Evaporation, processing (EtOAc) and process flash chromatography, the 6-alkoxyl group purine that obtains wishing.
C) aminoderivative: the solution that in the test tube of sealing 6-chloropurine and alkylamine is formed in MeOH is heated to 100 ℃ and heated 16 hours.Evaporation, processing (EtOAc) and process flash chromatography, the 6-alkoxyl group purine that obtains wishing.
General step 1.4: methylating on purine C-6 position
(the 2M solution in the toluene 0.45mmol) is handled 6-aluminium purine (0.2mmol) and four (triphenylphosphinyls) and close the suspension that palladium (0.02mmol) forms in exsiccant THF (3mL) with trimethyl aluminium under nitrogen atmosphere.With gained vlil 3h, be cooled to room temperature, with toluene (5mL) dilution, use ammonium chloride (1mmol) cancellation afterwards again with methyl alcohol (0.5mL).With reflux 2h and filtering through plug of celite while hot of mixture heating up.Evaporation is also passed through preparation property TLC purifying, obtains the 6-methyl purine.Referring to J.Med.Chem.1999,42,2064-2086.
The reductive dehalogenationization of general step 1.5:6-halo purine
Be dissolved in 6-halo purine derivative in the acetic acid and add the 5%Pd/C of catalytic amount, under the room temperature at H 2The 1h that stirs the mixture under the atmosphere (1psi), evaporation and purifying obtain the dehalogenation derivative.
The acylations of general step 1.6:2-amino-purine
The 2-aminopurine derivative is dissolved in the acetic anhydride, and the vitriol oil with catalytic amount under the room temperature was handled 1 hour.Handle (EtOAc), evaporation and purifying, obtain 2-acetamido-pyridine.
2. The general step of conversion pyridine ring
General step 2.1: the preparation of pyridine N-oxides
With pyridine derivate (1.0mmol) solution of ice bath cooling methylene dichloride or chloroform (5mL), divide three parts of treatment soln and make it be warming up to room temperature with m-CPBA (1.1-3mmol).Use the dichloromethane extraction mixture, and wash with water again after washing with the NaOH aqueous solution.Dry (Na 2SO 4) and concentrate, obtain pyridine N-oxides.
The preparation of general step 2.2:2-(acetoxy-methyl) pyridine
With the vlil 0.5h of 2-PICOLINE N-OXIDES (1.0mmol) in acetic anhydride (5mmol).Handle (EtOAc), dry (MgSO 4), evaporation and with preparation property TLC or flash chromatography purifying, obtain 2-(acetoxy-methyl) pyridine.
The preparation of general step 2.3:2-(hydroxymethyl) pyridine
With 2-acetoxy-methyl-pyridine derivate and solid K 2CO 3The suspension that forms in methyl alcohol is heated to 50 ℃ and heated 5-30 minute.Evaporation, processing (EtOAc) and dry (MgSO 4), obtain 2-(hydroxymethyl) pyridine.
The preparation of general step 2.4:2-(chloromethyl) pyridine
110 ℃ are stirred POCl down 32-hydroxymethyl-pyridine (10g) suspension 1.5h (30mL).The toughening oil of gained is cooled in room temperature and the impouring frozen water (500g).With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain being generally violet oil or solid 2-(chloromethyl) pyridine, its not purified just use.
The preparation of general step 2.5:2-(brooethyl) pyridine
The solution that 2-(hydroxymethyl) pyridine (1.0mmol) and triphenylphosphine (1.2mmol) are formed in methylene dichloride or chloroform (5mL) is cooled to 0 ℃.Drip CBr 4Methylene dichloride (1.5mmol) or chloroformic solution stir gained mixture 0.5-1h down at 0 ℃.Through the flash chromatography purifying, obtain 2-(brooethyl) pyridine after handling.
The O-alkylation of general step 2.6:3-or 4-pyridone
Stir pyridone, alkylogen (1.1 equivalent), alkali (K down at 23-80 ℃ 2CO 3, KOH or NaH 1.2-2 equivalent) and mixture 5-30 minute of solvent (THF or DMF).Handle (EtOAc), dry (Na 2SO 4) and evaporation, obtaining thick 4-(alkoxyl group) pyridine, it is by preparation property TLC or flash chromatography purifying.
General step 2.7: the preparation of salt
Method 1: (1: 6,300mL) middle heating free alkali (40mmol) was until its dissolving at MeOH.At room temperature drip H 3PO 4Solution in MeOH (40mmol).Stirred the mixture 10 minutes, and evaporating solvent obtains being brilliant white solid pyridinium phosphate.Can also use following solvent: THF, EtOH or i-PrOH.
Method 2: heating free alkali (50mmol) is until its dissolving in i-PrOH (6L).Make solution be cooled to room temperature and slowly drip HCl solution among the i-PrOH (75mmol).Hydrochloride crystallizes out from solution in the several minutes, filters and collects, and washing (acetone) is also dry.Can also prepare vitriol and mesylate in this way.
Can also in the alcoholic solution of pyridine or free alkali derivative, add CH 3COCl prepares hydrochloride.
Method 3: in the suspension of free alkali (5mmol) in MeOH (50mL), slowly drip the solution of methylsulfonic acid in MeOH (75mmol).The mixture clarification that becomes in the several minutes, add i-PrOH (50-100mL) then salt be precipitated out, filter and collect, with i-PrOH, ether washing and drying.
These methods can be used to prepare all other salt.
3. The general step of conversion phenyl ring
General step 3.1: the halogenation of phenyl ring
Variant 1: use Br under the room temperature 2Aromatics solution in (1.3 equivalent) the processing MeOH/THF/ acetic ester damping fluid (in each AcOH and AcONa, being 1N) 5 minutes.On rotatory evaporator, remove excessive bromine and solvent.Handle (CHCl 3) and through flash chromatography, the bromobenzene that obtains wishing.
Variant 2: the solution in acetic acid is heated to 40-90 ℃ and heat 0.3-1h with aromatics (7mmol) and N-halogenated succinimide imide (NCS, NBS or NIS, 1.06 equivalents).Evaporation, processing (EtOAc) and process flash chromatography, the halogeno-benzene that obtains wishing.
General step 3.2: the preparation of benzylalcohol
According to Bhaskar etc., J.Org.Chem.1991,56, the step that provides among the 5964-5965 is reduced to corresponding benzylalcohol with benzoic acid derivative.
4. Specific embodiment
Embodiment 59. purine are in the alkylation of N-9 and N-7 position
Under 70 ℃, use K 2CO 3(31.2mmol) handle purine (28.4mmol), the suspension of benzyl halide (28.7mmol) in exsiccant DMF (80mL).With the EtOAc extraction and through chromatogram EtOAc/ hexane (1: 1), obtain the alkylate of pure N-9 and N-7 position.All HPLC of single following parameters have all implemented:
HPLC post: 18,5 microns of Zorbax 300SB-C, 4.6 * 150mm
HPLC instrument: Agillent 1100
HPLC reagent A: 0.1%TFA/ water
HPLC reagent B:0.05%TFA/CH 3CN
HPLC method: 5%B-100%B in 7 minutes
Prepared following compounds in this way.
1.16-chloro-9-(2,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.194min。
1.26-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purine-2-base amine.HPLCR.t.5.194min。
1.36-chloro-9-(2,5-two chloro-benzyls)-9H-purine-2-base amine.HPLC?R.t.5.846min。
1.46-chloro-9-(2,5-two chloro-benzyls)-9H-purine-2-base amine.HPLC?R.t.5.982min。
1.56-bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.4.947min。
1.66-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine.HPLC?R.t.5.327min。
1.76-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.4.878min。
1.86-chloro-9-(2,3,5-three fluoro-benzyls)-9H-purine-2-base amine.HPLC?R.t.5.414min。
1.96-chloro-9-(3,5-two chloro-benzyls)-9H-purine-2-base amine.HPLC?R.t.6.074min。
1.106-chloro-9-(3,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.257min。
(1.119-2-bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine.HPLC?R.t.6.026min。
1.126-chloro-9-(2,6-two bromo-3,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.6.022min。
1.136-chloro-9-(3-methoxyl group-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.136min。
1.146-chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.445min。
1.156-chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.435min。
1.166-chloro-9-(6-chloro-benzo [1,3] dioxole-5-ylmethyl)-9H-purine-2-base amine.HPLC?R.t.5.506min。
1.176-chloro-9-(4-methoxyl group-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.067min。
1.184-chloro-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine.HPLC?R.t.5.683min。
1.196-bromo-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.5.676min。
1.206-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine.HPLC?R.t.3.941min。
(1.219-2-bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine.HPLC?R.t.5.458min。
1.224-chloro-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine.HPLC?R.t.4.464min。
1.236-chloro-9-(2,3-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.5.200min。
1.246-chloro-9-(3,4-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.4.753min。
(1.254-2-amino-6-chloro-purine-9-ylmethyl)-methyl benzoate.HPLC?R.t.5.052min。
1.266-chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.4.939min。
The halogenation of embodiment 60. purine
Add bromine or N-neoprene imide or N-iodine succimide (8.7mmol) in purine (6.6mmol) solution in acetate buffer solution/MeOH/THF or acetic acid or methylene dichloride.Though bromination can at room temperature be carried out, chlorination and iodate can be finished in 2 hours under 60 ℃-90 ℃.Use and the identical HPLC condition described in the embodiment 59.
Prepared following compounds in this way:
2.18-bromo-6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.6.150min。
2.28-bromo-6-chloro-9-(3,4-dimethoxy-2-nitro-benzyl)-9H-purine-2-base amine.HPLC?R.t.6.040min。
2.38-bromo-6-chloro-9-(3,4-two chloro-benzyls)-9H-purine-2-base amine.HPLC?R.t.6.878min。
2.46-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.5.616min。
2.56-chloro-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.5.626min。
2.66-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.5.793min。
2.78-bromo-9-(2-bromo-3,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-base amine.HPLC?R.t.5.720min。
(2.89-2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine.HPLC?R.t.5.987min。
(2.99-2,6-two bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine.HPLCR.t.6.676min。
(2.109-2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine.HPLC?R.t.6.248min。
(2.119-2,6-two bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine.HPLCR.t.6.952min。
2.126,8-two chloro-9-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.6.859min。
2.136-chloro-9-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.6.100min。
2.146-chloro-9-(2-iodo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.5.887min。
The displacement of embodiment 61.6-halogenation-purine
Can use known steps, for example as J.Med.Chem.1999,42, the description among the 2064-2086 is with H, R, NHR, OR, SR displacement 6-halogenation purine.Use and the identical HPLC condition described in the embodiment 59.
Prepared following compounds in this way:
(3.19-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLC?R.t.4.123min。
3.22-amino-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-6-mercaptan.HPLCR.t.4.931min。
3.32-amino-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-6-alcohol.HPLCR.t.4.610min。
(3.49-2-bromo-3,4,5-trimethoxy-benzyl)-6-ethyl sulfane base-9H-purine-2-base amine.HPLC?R.t.6.039min。
3.56-methoxyl group-9-(3,4,5-trimethoxy-benzyl)-9H-purine.HPLC?R.t.5.020min。
(3.69-3,4,5-trimethoxy-benzyl)-9H-purine-6-base amine.HPLC?R.t.4.248min。
(3.79-3,4,5-trimethoxy-benzyl)-9H-purine-2, the 6-diamines.HPLC?R.t.4.209min。
(3.89-2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine-2-base amine.HPLC?R.t.5.229min。
(3.99-2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2, the 6-diamines.HPLC?R.t.4.884min。
3.106-methoxyl group-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.HPLCR.t.4.489min。
(3.11N-[9-2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine-2-yl]-the N-methylacetamide.HPLC?R.t.6.178min。
The acylations of embodiment 62.2-amino-purine
Under the room temperature, in acetic anhydride, use the vitriol oil of catalytic amount, or can be with 2-amino-purine acylations in the nitrosonitric acid of acetic acid and catalytic amount.Use and the identical HPLC condition described in the embodiment 59.
Prepared following compounds in this way:
4.1N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-yl]-ethanamide.HPLC?R.t.5.744min。
(4.2N-[9-2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-yl]-ethanamide.HPLC?R.t.5.603min。
Embodiment 63.N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-yl]-the methylating of N-methylacetamide or compound 4.2.
In compound 4.2 (the foregoing description 62) and the suspension of methyl iodide in DMF, add NaH.Obtain 5 with the EtOAc extraction and through chromatogram.HPLC?R.t.6.177min。
Synthesizing of embodiment 64.6-methyl purine
Purine (0.19mmol) and four (triphenylphosphinyls) are closed palladium (0.019mmol) suspend and be among the dry THF (3mL), (the 2M solution in the toluene 0.44mmol) is handled and is obtained title compound with trimethyl aluminium in nitrogen afterwards.Before being cooled to room temperature, solution earlier solution was refluxed 3 hours.With toluene (5mL) diluted reaction mixture, use methyl alcohol (0.5mL) and ammonium chloride subsequently (1mmol) cancellation reaction afterwards.The mixture backflow was also filtered on diatomite in 2 hours while hot.Referring to J.Med.Chem, 1999,42 (12), 2064-2086.
Prepared following compounds in this way:
(6.19-2-chloro-3,4,5-trimethoxy-benzyl)-6-methyl-9H-purine-2-base amine.HPLCR.t.4.800min。
Embodiment 65:9-(4-bromo-3,5-dimethyl-pyridine-2-yl)-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 4-bromo-2-brooethyl-3,5-dimethyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.301min。 1H-NMR?(CDCl 3)：δ8.19(s，1H)，7.88(s，1H)，5.41(s，2H)，5.06(s，2H)，2.53(s，3H)，2.39(s，3H)。m/z(％)367.1(M+1，75％)，369.1(M+3，100％)，371.1(M+5，25％)
Alkylating agent, 4-bromo-2-brooethyl-3,5-dimethyl-pyridine itself can be according to any preparations of following three kinds of methods:
Method 1
Step 1:2,3,5-collidine-N-oxide compound
According to general step 2.1 oxidations 2,3, the 5-collidine obtains 2,3,5-collidine-N-oxide compound.Productive rate: 70%.HPLC?Rt：3.96min。 1H-NMR(CDCl 3)：δ8.03(s，1H)，6.90(s，1H)，2.47(s，3H)，2.31(s，3H)，2.24(s，3H)。m/z(％)138.2(M+1，100％)。Rf(20％MeOH/EtOAc)：0.35。
Step 2:4-bromo-2,3,5-collidine-N-oxide compound
With 2,3, and 5-collidine-N-oxide compound (1.3g, 10mmol) and K 2CO 3(2.9g 20mmol) is suspended in 10mL CCl 4In.Dripping bromine (1mL, 20mmol), and with the mixture heating up 2h that refluxes.Handle (EtOAc) and, obtain being solid product (1.05g, productive rate 51%) through flash chromatography (10%MeOH/EtOAc).HPLC?Rt：5.239min。 1H-NMR(CDCl 3)：δ8.06(s， 1H)，2.56(s，3H)，2.43(s，3H)，2.31(s，3H)。m/z(％)216.2(M+1，100％)，218.2(M+3，100％)。Rf(20％MeOH/EtOAc)：0.45。
Step 3: acetic acid 4-bromo-3,5-dimethyl-pyridine-2-base methyl esters
With 4-bromo-2,3, (0.25g 11mmol) is dissolved in the acetic anhydride (5mL) and with vlil 30min 5-collidine-N-oxide compound.Handle and through flash chromatography (10% hexane/EtOAc), obtain product (0.27g, productive rate 96%).Rf (50% hexane/EtOAc): 0.70.HPLC?Rt：4.759min。 1H-NMR(CDCl 3)：δ8.26(s，1H)，5.27(s，2H)，2.46(s，3H)，2.41(s，3H)，2.14(s，3H)。
Step 4:4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol
With acetic acid 4-bromo-3, and 5-dimethyl-pyridine-2-base methyl esters (0.26g, 1.0mmol) and K 2CO 3(excessive) suspension in MeOH (5mL) is heated to 50 ℃ of 15min.Handle (CHCl 3), (eluent: 100%EtOAc) filtration and evaporation obtain the title compound (0.19g, productive rate 88%) into white solid with silicagel pad.Rf (50% hexane/EtOAc): 0.5.HPLC?Rt：3.80min。 1H-NMR(CDCl 3)：δ8.23(s，1H)，4.70(s，2H)，2.46(s，3H)，2.30(s，3H)。
Step 5:4-bromo-2-brooethyl-3,5-dimethyl-pyridine
According to general step 2.5, by 4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol obtains title compound.HPLC?Rt：6.323min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.63(s，2H)，2.52(s，3H)，2.40(s，3H)。
Method 2:
Step 1:2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol
Obtain title compound according to the step of describing among the patent WO 99/10326 of Tarbit etc.
Step 2:4-bromine 2-chloromethyl-3,5-dimethyl-pyridine
Under 130 ℃ with 2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol (8.2g, 47.8mmol) and POBr 3(60g, pure mixture 209mmol) stirred 3 hours.The toughening oil of gained is cooled in room temperature and the impouring frozen water.With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain being purple solid title compound (8.7g, productive rate 78%) its not purified just use.HPLC?Rt：6.028min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，4.62(s，2H)，2.50(s，3H)，2.38(s，3H)。
Method 3:
Step 1:4-bromo-2-chloromethyl-3,5-dimethyl-pyridine
With 2-chloromethyl-4-methoxyl group-3, (3.24g is 14.6mmol) at PBr for 5-dimethyl-pyridine under nitrogen atmosphere 3Suspension in (8.0mL, 85.1mmol, 5.8 equivalents) is heated to 80 ℃.The DMF (0.50mL, 6.4mmol, 0.44 equivalent) that adds catalytic amount, during suspension become orange solution rapidly.After 40 minutes, HPLC judges that reaction is incomplete yet.Temperature is increased to 110 ℃ also prolongs reaction 30 minutes, react completely this moment.In mixture impouring ice, use NH 4The OH strong solution is alkalescence, and is extracted among the EtOAc.Wash with water, dry (salt solution, MgSO 4) and concentrate, obtain title compound (1.51g, 44%) into pink solid, use 1H-NMR judges that it contains 10% impurity.Crude product uses without just being further purified. 1H-NMR(CDCl 3)：δ8.19(s，1H)，4.59(s，2H)，2.48(s，3H)，2.37(s，3H)。
Embodiment 66:9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine, phosphoric acid salt
According to general step 2.7, use H 3PO 4Handle 9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine, obtain title compound.HPLC?Rt：5.294min。 1H-NMR(d 6-DMSO)：δ8.12(s，1H)，8.09(s，1H)，6.83(s，2H)，5.47(s，2H)，2.49(s，3H)，2.29(s，3H)。
Embodiment 67:9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine, hydrochloride
According to general step 2.7, handle 9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine with HCl, obtain title compound.HPLC?Rt：5.294min。 1H-NMR(d 6-DMSO)：δ8.13(s，1H)，8.12(s，1H)，5.47(s，2H)，5.47(s，2H)，2.49(s，3H)，2.30(s，3H)。
Embodiment 68:9-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine
According to general step 2.1 oxidation 9-(4-bromo-3,5-dimethyl-pyridine-2-yl)-6-chloro-9H-purine-2-base amine, obtain title compound.HPLC?Rt：4.916min。 1H-NMR(CDCl 3)：δ8.46(s，1H)，8.07(s，1H)，5.57(s，2H)，5.03(s，2H)，2.81(s，3H)，2.35(s，3H)。
Embodiment 69:6-bromo-9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
50 ℃ stir down 6-bromo-9H-purine-2-base amine (2.4g, 11mmol), 4-bromo-2-chloromethyl-3, the 5-lutidine (3.5g, 15mmol), K 2CO 3(2.07g, 15mmol) and the mixture 2h of DMF (50mL).Handle ice through flash chromatography, obtain title compound (2.6g, 56%) into white solid.HPLC?Rt：5.415min。 1H-NMR(CDCl 3)：?δ8.17(s，1H)，7.88(s，1H)，5.38(s，2H)，5.05(s，2H)，2.51(s，3H)，2.37(s，3H)。
Embodiment 70:6-bromo-9-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.1 oxidation 6-bromo-9-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl), obtain title compound (productive rate 52%).Rf(100％EtOAc)：0.1。HPLC?Rt：4.978min。 1H-NMR(CDCl 3)：δ8.47(s，1H)，8.07(s，1H)，5.56(s，2H)，5.06(s，2H)，2.81(s，3H)，2.35(s，3H)。
Embodiment 71:2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl--pyridine-4-alcohol
According to general step 1.1, with 2-chloromethyl-3,5-lutidine-4-alcohol, alkylation 6-chloro-9H-purine-2-base amine obtains title compound.HPLC?Rt：3.624min。 1H-NMR(d 6-DMSO)：δ8.07(s，1H)，7.47(s，1H)，6.90(s，2H)，5.20(s，2H)，2.00(s，3H)，186(s，3H)。
Embodiment 72:6-chloro-9-(4-oxyethyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Use general step 2.6, use iodoethane, with 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol carries out the O-alkylation, obtains title compound.HPLC?Rt：4.321min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.90(s，1H)，5.34(s，2H)，5.12(s，2H)，3.90(q，2H)，2.31(s，3H)2.26(s，3H)，1.44(t，3H)。
Embodiment 73:9-(4-allyl group-3,5-dimethyl-pyridine-2-ylmethyl)-6-chloro-9H-purine-2-base amine
Use general step 2.6, use chlorallylene, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLC?Rt：4.417min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，7.90(s，1H)，6.03-6.10(m，?1H)，5.40-5.44(dd，1H)，5.34(s，2H)，5.29-5.32(dd，1H)，5.19(s，2H)，4.34-4.36(m，2H)，2.30(s，3H)2.25(s，3H)。
Embodiment 74:6-chloro-9-[4-(2-oxyethyl group-oxyethyl group)-3,5-dimethyl-pyridine-2-ylmethyl]-9H-purine-2-base amine
Use general step 2.6, use ethoxy ethyl chloride, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLCRt：4.388min。 1H-NMR(CDCl 3)：δ8.19(s，1H)，7.89(s，1H)，5.33(s，2H)，5.14(s，2H)，3.97-4.00(t，2H)，3.73-3.76(t，2H)，3.56-3.61(q，2H)，2.33(s，3H)，2.26(s，3H)，1.22-1.26(t，3H)。
Embodiment 75:6-chloro-9-(4-isopropoxy-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Use general step 2.6, use isopropyl iodide, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLC?Rt：4.571min。 1H-NMR(CDCl 3)：δ8.17(s，1H)，7.89(s，1H)，5.32(s，2H)，5.06(s，2H)，4.20(m，1H)，2.26(s，3H)2.22(s，3H)，1.28-1.30(d，3H)。
Embodiment 76:6-chloro-9-(4-cyclo propyl methoxy-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Use general step 2.6, use the cyclopropyl methyl-iodide, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLCRt：4.709min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，7.90(s，1H)，5.34(s，2H)，5.09(s，2H)，3.68-3.70(d，2H)，2.32(s，3H)2.27(s，3H)，1.23-1.31(m，1H)，0.63-0.68(m，2H)，0.30-0.33(m，2H)。
Embodiment 77:6-chloro-9-[3,5-dimethyl-4-(3-methyl-butoxy)-pyridine-2-ylmethyl]-9H-purine-2-base amine
Use general step 2.6, with 3-methyl butyl bromine, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLC?Rt：5.425min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.90(s，1H)，5.34(s，2H)，5.07(s，2H)，3.82-3.86(t，2H)，2.31(s，3H)2.26(s，3H)，1.84-1.91(m，1H)，1.71-1.74(q，2H)，1.00(s，3H)，0.98(s，3H)。
Embodiment 78:6-chloro-9-(4-isobutoxy-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Use general step 2.6, use isobutyl bromide, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLC?Rt：4.321min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.90(s，1H)，5.34(s，2H)，5.12(s，2H)，3.58-3.56(d，2H)，2.30(s，3H)2.26(s，3H)，1.09(s，3H)，1.08(s，3H)。
Embodiment 79: acetic acid 2-[2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridin-4-yl oxygen base]-ethyl ester
Use general step 2.6, with acetic acid 2-bromine ethyl ester, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLCRt：4.103min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.90(s，1H)，5.35(s，2H)，5.10(s，2H)，4.42(t，2H)，4.05(t，2H)，2.34(s，3H)2.27(s，3H)，2.13(s，3H)。
Embodiment 80: acetic acid 3-[2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridin-4-yl oxygen base]-propyl ester
Use general step 2.6,, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3 with acetic acid 2-chlorine propyl ester, 5-dimethyl-pyridine-4-alcohol quilt, the O-alkylation obtains title compound.HPLCRt：4.414min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.91(s，1H)，5.34(s，2H)，5.12(s，2H)，4.34(t，2H)，3.90(t，2H)，2.31(s，3H)，2.25(s，3H)，2.15(m，1H)，2.09(s，3H)。
Embodiment 81:6-chloro-9-(3,5-dimethyl-4-propoxy--pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.6, make 2-(2-amino-6-chloro-purine-9-ylmethyl)-3,5-dimethyl-pyridine-4-alcohol is obtained title compound by the O-alkylation.HPLC?Rt：4.644min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.91(s，1H)，5.34(s，2H)，5.12(s，2H)，3.80-3.76(t，2H)，2.31(s，3H)，2.26(s，3H)，1.85(m，2H)，1.07-1.10(t，3H)。
Embodiment 82:6-chloro-9-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:4-chloro-2-chloromethyl-3, the 5-lutidine
According to step 2.4, use PCl 3Handle 2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol obtains title compound (productive rate 74%).HPLC?Rt：5.543min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，4.71(s，2H)，2.48(s，3H)，2.36(s，3H)。
Step 2:6-chloro-9-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
With 6-chloro-9H-purine-2-base amine (7g, 41mmol), 4-chloro-2-chloromethyl-3, the 5-lutidine (8.2g, 43mmol), K 2CO 3(10g, 72mmol) and the mixture heating up to 50 of DMF (200mL) ℃ and heat 2h.Water (200mL) diluted reaction mixture also filters the throw out of collecting gained, washes with water and drying, obtains the title compound (11.7g, productive rate 88%, purity 90%) into beige solid.HPLC?Rt：5.167min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，7.90(s，1H)，5.40(s，2H)，5.07(s，2H)，2.49(s，3H)，2.37(s，3H)。
Embodiment 83:6-chloro-9-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.1, obtain title compound by oxidation 6-chloro-9-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine.HPLC?Rt：4.813min。 1H-NMR(d 6-DMSO)：δ8.31(s，1H)，8.20(s，1H)，6.91(s，2H)，5.41(s，2H)，2.73(s，3H)，2.26(s，3H)。
Embodiment 84:6-chloro-9-(3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1: acetic acid 3,5-dimethyl-pyridine-2-base methyl esters
According to general step 2.2, by 2,3,5-collidine-N-oxide compound (referring to embodiment 1) preparation title compound.HPLC?Rt：2.916min。 1H-NMR(CDCl 3)：δ8.30(s，1H)，7.33(s，1H)，5.22(s，2H)，2.34(s，3H)，2.32(s，3H)，2.13(s，3H)。
Step 2:3,5-dimethyl-pyridine-2-base methyl alcohol
According to general step 2.3, by Dichlorodiphenyl Acetate 3,5-dimethyl-pyridine-2-base methyl esters takes off acetyl and obtains title compound.HPLC?Rt：2.909min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，7.30(s，1H)，4.85(br?s，1H)，4.67(s，2H)，2.33(s，3H)，2.20(s，3H)。
Step 3:2-brooethyl-3,5-dimethyl-pyridine
According to general step 2.5, by 3,5-dimethyl-pyridine-2-base methyl alcohol obtains title compound.HPLC?Rt：3.895min。 1H-NMR(CDCl 3)：δ8.3(s，1H)，7.3(s，1H)，4.61(s，2H)，2.41(s，3H)，2.33(s，3H)。
Step 4:6-chloro-9-(3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-3,5-lutidine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.760min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.89(s，1H)，7.30(s，1H)，5.32(s，2H)，5.05(s，2H)，2.36(s，3H)，2.29(s，3H)。
Embodiment 85:6-bromo-9-(4-methoxyl group 3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-lutidine, alkylation 6-bromo-9H-purine-2-base amine obtains title compound.HPLC?Rt：4.138min。 1H-NMR(CDCl 3)：δ8.21(s，1H)，7.91(s，1H)，5.34(s，2H)，5.12(s，2H)，3.77(s，3H)，2.32(s，3H)，2.27(s，3H)。m/z(％)363.2(M+1，100％)，365.2(M+3，100％)。
Embodiment 86:6-bromo-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, phosphoric acid salt
According to general step 2.7, use H 3PO 4Handle 6-bromo-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, obtain title compound.HPLC?Rt：4.138min。 1H-NMR(CDCl 3)：δ8.07(s，1H)，8.02(s，1H)，6.84(s，2H)，5.35(s，2H)，3.73(s，3H)，2.29(s，3H)，2.15(s，3H)。m/z(％)363.2(M+1，100％)，365.2(M+3，100％)。
Embodiment 87:6-bromo-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, hydrochloride
According to general step 2.7, handle 6-bromo-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine with HCl, obtain title compound.HPLC?Rt：4.138min。 1H-NMR(d 6-DMSO)：δ8.44(s，1H)，8.26(s，1H)，5.57(s，2H)，3.96(s，3H)，2.35(s，3H)，2.34(s，3H)。
Embodiment 88:6-bromo-9-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.1,, obtain title compound by oxidation 6-bromo-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine.HPLC?Rt：4.439min。 1H-NMR(CDCl 3)：δ8.55(s，1H)，8.06(s，1H)，5.50(s，2H)，5.12(s，2H)，3.76(s，3H)，2.60(s，3H)，2.25(s，3H)。m/z(％)379.1(M+1，100％)，381.1(M+3，100％)。
Embodiment 89:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Method 1
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-lutidine (or its HCl salt), alkylation 6-chloro-9H-purine-2-base amine obtains title compound.
Method 2
Can also be according to step 2.6 (KOH, MeI, DMF, 80 ℃, 5 minutes), obtain title compound by O-6-chloro-9-(4-hydroxyl-3,5-dimethyl-pyridine-2-the ylmethyl)-9H-purine-2-base amine that methylates.HPLC?Rt：3.980min。 1H-NMR(CDCl 3)：δ8.19(s，1H)，7.88(s，1H)，5.32(s，2H)，5.07(s，2H)，3.75(s，3H)，2.29(s，3H)，2.24(s，3H)。
Method 3
Step 1:(4-methoxyl group-3,5-dimethyl-pyridine-2-yl)-methylamine
With the chloromethyl of the 2-in the 7N methanol ammonia-4-methoxyl group-3,5-dimethyl-pyridine hydrochloride solution is placed in the autoclave and at 100 ℃ and heats 16h.Concentrate and the process flash chromatography, obtain title compound (productive rate 76%) into green solid.HPLC?Rt：3.773min。 1H-NMR(CDCl 3)：δ8.19(s，1H)，4.35(s，2H)，3.76(s，3H)，2.24(s，3H)，2.18(s，3H)。
Step 2:6-chloro-4-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-pyrimidine-2,4, the 5-triamine
With 4,6-two chloro-pyrimidines-2,5-diamines (referring to Seela etc., Helv.Chim.Acta.1986,69,1602-1613 and US patent No.5,917,042), 4-methoxyl group-3,5-dimethyl-pyridine-2-yl)-methylamine and Et 3The vlil 1h of N in butanols obtains title compound.HPLCRt：3.761min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，7.15(s，1H)，4.60(s，2H)，4.56-4.55(d，2H)，3.80(s，3H)，3.00(s，2H)，2.28(s，3H)，2.27(s，3H)。
Step 3:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Can in the presence of acid, prepare purine with the tri-methyl ortho formate cyclisation.Referring to similar reaction, embodiment 48.
Embodiment 90:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, phosphoric acid salt
According to general step 2.7, use H 3PO 4Handle 6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, obtain title compound.HPLC?Rt：4.003min。 1H-NMR(d 6-DMSO)：δ8.06(s，1H)，8.03(s，1H)，6.83(s，2H)，5.36(s，?2H)，3.74(s，3H)，2.29(s，3H)，2.16(s，3H)。
Embodiment 91:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, vitriol
According to general step 2.7, use H 2SO 4Handle 6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, obtain title compound.HPLC?Rt：3.999min。 1H-NMR(d 6-DMSO)：δ8.36(s，1H)，8.15(s，1H)，5.52(s，2H)，3.93(s，3H)，2.31(s，3H)，2.30(s，3H)。
Embodiment 92:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, hydrochloride
According to general step 2.7, handle 6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine with HCl, obtain title compound.HPLC?Rt：4.093min。 1H-NMR(d 6-DMSO)：δ8.38(s，1H)，8.23(s，1H)，5.55(s，2H)，3.93(s，3H)，2.34(s，3H)，2.31(s，3H)。
Embodiment 93:6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, mesylate
According to general step 2.7, use MeSO 3H handles 6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine, obtains title compound.HPLC?Rt：4.093min。 1H-NMR(d 6-DMSO)：δ8.38(s，1H)，8.17(s，1H)，5.54(s，2H)，3.95(s，3H)，2.36(s，3H)，2.34(s，3H)，2.33(s，3H)。
Embodiment 94:N-[6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-yl]-ethanamide
With a dense H 2SO 46-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine in the processing acetic anhydride (2.2g)-(80mg, 0.25mmol) suspension also at room temperature stirred 5 minutes 2-base amine.Handle (EtOAc), dry (MgSO 4) and evaporation, obtain title compound into white solid.HPLC?Rt：4.093min。 1H-NMR(CDCl 3)：?δ8.20(s，1H)，8.10(s，1H)，5.46(s，2H)，3.78(s，3H)，2.54(s，3H)，2.38(s，3H)，2.27(s，3H)。
Embodiment 95:6-chloro-9-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.1, obtain title compound by oxidation 6-chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine.HPLC?Rt：4.435min。 1H-NMR(CDCl 3)：δ8.55(s，1H)，8.06(s，1H)，5.52(s，2H)，5.07(s，2H)，3.76(s，3H)，2.61(s，3H)，2.25(s，3H)。m/z(％)335.1(M+1，100％)，337.1(M+3，34％)。
Embodiment 96:6-chloro-9-(4-methoxyl group-3,5-dimethyl-1-methoxyl group-pyridine-2-methyl)-9H-purine-2-base amine Methylsulfate
With the 6-chloro-9-among the DCM (10mL) (4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine (0.2g, 0.56mmol) suspension reflux.Drip methyl-sulfate (1.12mmol) (Tarbit WO99/10326) and continue heating 3h.Filter and washing (hot acetone), obtain title compound into beige solid.HPLC?Rt：3.379min。 1H-NMR(CDCl 3)：δ9.68(s，1H)，9.40(s，1H)，5.85(s，2H)，4.42(s，3H)，4.15(s，3H)，4.12(s，3H)，2.70(s，3H)，2.47(s，3H)。
Embodiment 97:6-chloro-9-(6-chloro-4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Method 1
According to general step 2.4, handle 6-chloro-9-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine with POCl3.Obtain title compound through flash chromatography into white solid.HPLC?Rt：5.741min。 1H-NMR(CDCl 3)：δ7.94(s，1H)，5.29(s，2H)，5.05(s，2H)，3.74(s，3H)，2.30(s，3H)，2.28(s，3H)。
Method 2
Step 1:2-chloromethyl-4-methoxyl group-3,5-lutidine-1-oxide compound
According to general step 2.1, by oxidation 2-chloromethyl-4-methoxyl group-3, the 5-lutidine obtains title compound.HPLC?Rt：4.462min。 1H-NMR(CDCl 3)：δ8.05(s，1H)，4.93(s，2H)，3.77(s，3H)，2.37(s，3H)，2.24(s，3H)。
Step 2:2-chloro-6-chloromethyl-4-methoxyl group-3, the 5-lutidine
According to general step 2.4, handle 2-chloromethyl-4-methoxyl group-3 with POCl3,5-lutidine-1-oxide compound obtains title compound.HPLC?Rt：6.757min。 1H-NMR(CDCl 3)：δ4.64(s，2H)，3.79(s，3H)，2.35(s，3H)，2.33(s，3H)。
Step 3:6-chloro-9-(6-chloro-4-methoxyl group-3,5-lutidine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloro-6-chloromethyl-4-methoxyl group-3,5-lutidine, alkylation 6-chloro-9H-purine-2-base amine obtains title compound.
Embodiment 98:6-chloro-9-(5-methoxyl group-4-methoxymethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine
Step 1: acetic acid 3-acetoxyl group-5-hydroxymethyl-2-methyl-pyridin-4-yl methyl esters
According to Morisawa etc., J.Med.Chem.1974,17, the step of reporting among the 1083-1086 obtains title compound.HPLC?Rt：3.08min。 1H-NMR(CDCl 3)：δ8.41(s，1H)，5.20(s，2H)，4.80(s，2H)，2.40(s，3H)，2.38(s，3H)，2.03(s，3H)。
Step 2: acetic acid 3-acetoxyl group-5-brooethyl-2-methyl-pyridin-4-yl methyl esters
According to general step 2.5, obtain title compound by acetic acid-3-acetoxyl group-5-hydroxymethyl-2-methyl-pyridin-4-yl methyl esters.HPLC?Rt：5.332min。 1H-NMR(CDCl 3)：δ8.43(s，1H)，5.22(s，2H)，4.70(s，2H)，2.43(s，3H)，2.41(s，3H)，2.06(s，3H)。
Step 3:6-chloro-9-(5-acetoxyl group-4-acetoxy-methyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine
According to general step 1.1, with acetic acid 3-acetoxyl group-5-brooethyl-2-methyl-pyridin-4-yl methyl esters, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.498min。 1H-NMR(CDCl 3)：δ8.42(s，1H)，7.74(s，1H)，5.43(s，2H)，5.10(s，2H)，5.07(s，2H)，2.42(s，3H)，2.39(s，3H)，1.96(s，3H)。
Step 4:6-chloro-9-(5-hydroxy-4-hydroxymethyl ylmethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine
With the 6-chloro-9-among the MeOH (5-acetoxyl group-4-acetoxy-methyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine and K 2CO 3(excessive) suspension is heated to 50 ℃ and heated 15 minutes.Filter, handle (EtOAc) and obtain title compound by preparation property TLC purifying.HPLC?Rt：4.498min。 1H-NMR(d 3-DMSO)：δ8.08(s，1H)，7.74(s，1H)，6.95(s，1H)，5.31(s，2H)，4.74(s，2H)，2.31(s，3H)。
Step 5:6-chloro-9-(5-methoxyl group-4-methoxymethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine
With 6-chloro-9-(5-hydroxy-4-hydroxymethyl ylmethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine, MeI, K 2CO 3The mixture heating up to 50 of (excessive) and DMF ℃ also heated 15 minutes.Handle (EtOAc), dry (MgSO 4), evaporation and by preparation property TLC purifying, obtain title compound.HPLC?Rt：5.446min。 1H-NMR(CDCl 3)：δ8.35(s，1H)，7.70(s，1H)，5.35(s，2H)，5.25(s，2H)，5.15(s，2H)，3.80(s，3H)2.59(s，3H)，1.970(s，3H)。
Embodiment 99:6-chloro-9-(5-oxyethyl group-4-hydroxymethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine
With 6-chloro-9-(5-hydroxy-4-hydroxymethyl ylmethyl-6-methyl-pyridin-3-yl methyl)-9H-purine-2-base amine (referring to embodiment before), EtI (excessive), K 2CO 3The mixture heating up to 50 of (excessive) and DMF ℃ also heated 15 minutes.Handle (EtOAc), dry (MgSO 4), evaporation and by preparation property TLC purifying, obtain title compound.HPLC?Rt：3.720min。 1H-NMR(CDCl 3)：δ8.27(s，1H)，7.90(s，1H)，5.40(s，2H)，5.11(s，2H)，4.85(d，2H)，4.50(t，1H)，3.95(q，2H)，2.51(s，3H)1.45(t，3H)。
Embodiment 100:6-chloro-9-(3,5-dimethyl-4-amino-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:2-brooethyl-3,5-dimethyl-4-nitro-pyridine
According to general step 2.5, obtain title compound by (3,5-dimethyl-4-nitro-pyridine-2-yl)-methyl alcohol.HPLC?Rt：6.206min。 1H-NMR(CDCl 3)：δ8.46(s，1H)，4.64(s，2H)，2.38(s，3H)，2.33(s，3H)。
Step 2:6-chloro-9-(3,5-dimethyl-4-nitro-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-3,5-dimethyl-4-nitro-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：6.206min。 1H-NMR(CDCl 3)：δ8.40(s，1H)，7.94(s，1H)，5.40(s，2H)，5.05(s，2H)，2.40(s，3H)，2.27(s，3H)。
Step 3:6-chloro-9-(3,5-dimethyl-4-amino-pyridine-2-ylmethyl)-9H-purine-2-base amine
Under the room temperature with the 6-chloro-9-in the methyl alcohol (4,6-dimethyl-5-nitro-pyridin-3-yl methyl)-9H-purine-2-base amine and excessive V-Brite B (Na 2S 2O 4) suspension stirred 2 days.Before with the EtOAc extraction, evaporate MeOH earlier.Evaporation and with preparation property TLC (100%EtOAc) purifying obtains title compound.HPLC?Rt：3.544min。 1H-NMR(CDCl 3)：δ8.05(s，1H)，7.83(s，1H)，5.31(s，2H)，5.05(s，2H)，4.08(s，2H)，2.12(s，6H)。
Embodiment 101:6-chloro-9-(3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:3-methoxyl group-5-methoxymethyl-2,4-dimethyl-pyridine
0 ℃ down with MeI (2.28g, 15mmol) and NaH ((1g, 5.2mmol) solution 1h obtain title compound to 4-dimethyl-pyridine-3-alcohol hydrochloride for 0.6g, 50mmol) the 5-hydroxymethyl-2 among the processing DMF.HPLC?Rt：2.835min。 1H-NMR(CDCl 3)：δ8.16(s，1H)，4.44(s，2H)，3.75(s，3H)，3.41(s，3H)，2.53(s，3H)，2.32(s，3H)。
Step 2:3-methoxyl group-5-methoxymethyl-2,4-dimethyl-pyridine 1-oxide compound
According to general step 2.1, by oxidation 3-methoxyl group-5-methoxymethyl-2,4-dimethyl-pyridine obtains title compound.HPLC?Rt：4.181min。 1H-NMR(CDCl 3)：δ8.18(s，1H)，4.39(s，2H)，3.76(s，3H)，3.43(s，3H)，2.52(s，3H)，2.46(s，3H)。
Step 3: acetic acid 3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-base methyl esters
According to general step 2.2, handle 3-methoxyl group-5-methoxymethyl-2 with Ac2O, 4-dimethyl-pyridine 1-oxide compound obtains title compound.HPLC?Rt：4.062min。 1H-NMR?(CDCl 3)：δ8.32(s，1H)，5.27(s，2H)，4.47(s，2H)，3.80(s，3H)，3.43(s，3H)，2.34(s，3H)，2.25(s，3H)。
Step 4:(3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-yl)-methyl alcohol
According to general step 2.3, obtain title compound by acetic acid 3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-base methyl esters.HPLC?Rt：3.465min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.75(d，2H)，4.47(s，2H)，4.20(t，1H)，3.77(s，3H)，3.43(s，3H)，2.34(s，3H)。
Step 5:2-brooethyl-3-methoxyl group-5-methoxymethyl-4-methyl-pyridine
According to general step 2.5, obtain title compound by (3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-yl)-methyl alcohol.HPLC?Rt：4.498min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.695(s，2H)，4.42(s，2H)，3.86(s，3H)，3.40(s，3H)，2.31(s，3H)。
Step 6:6-chloro-9-(3-methoxyl group-5-methoxymethyl-4-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-3-methoxyl group-5-methoxymethyl-4-methyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.254min。 1H-NMR(CDCl 3)：δ8.210(s，1H)，7.96(s，1H)，5.40(s，2H)，5.05(s，2H)，4.42(s，2H)，3.78(s，3H)，3.40(s，3H)，2.31(s，3H)。
Embodiment 102:6-chloro-9-(5-chloro-6-methoxyl group-pyridin-3-yl methyl)-9H-purine-2-base amine
Step 1:(5-chloro-6-methoxyl group-pyridin-3-yl)-methyl alcohol
With (5,6-two chloro-pyridin-3-yls)-dissolve with methanol in the saturated NaOMe solution of MeOH and reflux spend the night.Evaporation MeOH, processing (EtOAc) and evaporation obtain title compound. 1H-NMR(CDCl：δ8.03(d，1H)，7.72(d，1H)，4.65(s，2H)，4.04(s，3H)。
Step 2:5-brooethyl-3-chloro-2-methoxyl group-pyridine
According to general step 2.5, obtain title compound by (5-chloro-6-methoxyl group-pyridin-3-yl)-methyl alcohol. 1H-NMR(CDCl 3)：δ8.05(d，1H)，7.70(d，1H)，4.42(s，2H)，4.02?(s，3H)。
Step 3:6-chloro-9-(5-chloro-6-methoxyl group-pyridin-3-yl)-9H-purine-2-base amine
According to general step 1.1, with 5-brooethyl-3-chloro-2-methoxyl group-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.256min。 1H-NMR(CDCl 3)：δ8.11(d，1H)，7.78(s，1H)，7.63(d，1H)，5.19(s，2H)，5.16(s，2H)，4.04(s，3H)。
Embodiment 103:6-chloro-9-(3,4-dimethoxy-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.777min。 1H-NMR(CDCl 3)：δ8.19(d，1H)，7.95(s，1H)，6.82(d，1H)，5.39(s，2H)，5.09(s，2H)，3.92(s，3H)，3.87(s，3H)。
Embodiment 104:6-chloro-9-(3-methoxyl group-6-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:(3-methoxyl group-6-methyl-pyridine-2-yl)-methyl alcohol
According to general step 2.6, obtain title compound by O-2-hydroxymethyl-6-methyl-pyridine-3-alcohol that methylates.HPLC?Rt：2.304min。 1H-NMR(CDCl 3)：δ7.05-7.11(m，2H)，4.72-4.71(d，2H)，4.47-4.49(t，1H)，3.84(s，3H)，2.51(s，3H)。
Step 2:2-brooethyl-3-methoxyl group-6-methyl-pyridine
According to general step 2.5, obtain title compound by (3-methoxyl group-6-methyl-pyridine-2-yl)-methyl alcohol.HPLC?Rt：4.361min。 1H-NMR(CDCl 3)：δ7.06-7.12(m，2H)，4.61(s，2H)，3.89(s，3H)，2.49(s，3H)。
Step 3:6-chloro-9-(3-methoxyl group-6-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-3-methoxyl group-6-methyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.777min。 1H-NMR(CDCl 3)：δ7.92(s，1H)，7.11(m，2H)，5.39(s，2H)，5.15(s，2H)，3.85(s，3H)，2.45(s，3H)。
Embodiment 105:6-chloro-9-(5-methoxyl group-4,6-dimethyl-pyridin-3-yl methyl)-9H-purine-2-base amine
Step 1:(5-methoxyl group-4,6-dimethyl-pyridin-3-yl)-methyl alcohol
According to general step 2.6, by the O-5-hydroxymethyl-2 that methylates, 4-dimethyl-pyridine-3-alcohol obtains title compound.HPLC?Rt：3.114min。 1H-NMR(CDCl 3)：δ8.08(s，1H)，4.67(s，2H)，3.74(s，3H)，2.49(s，3H)，2.33(s，3H)。
Step 2:5-brooethyl-3-methoxyl group-2,4-dimethyl-pyridine
According to general step 2.5, obtain title compound by (5-methoxyl group-4,6-dimethyl-pyridin-3-yl)-methyl alcohol.HPLC?Rt：2.873min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.50(s，2H)，3.764(s，3H)，2.54(s，3H)，2.37(s，3H)。
Step 3:6-chloro-9-(5-methoxyl group-4,6-dimethyl-pyridin-3-yl methyl)-9H-purine-2-base amine
According to general step 1.1, with 5-brooethyl-3-methoxyl group-2,4-dimethyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.7387min。 1H-NMR(CDCl 3)：δ8.25(s，1H)，7.63(s，1H)，5.39(s，2H)，5.11(s，2H)，3.73(s，3H)，2.55(s，3H)，2.22(s，3H)。
Embodiment 106:9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.434min。 1H-NMR(CDCl 3)：δ8.75(s，1H)，8.25(s，1H)，7.90(s，1H)，5.37(s，2H)，5.07(s，2H)，3.77(s，3H)，2.32(s，3H)，2.26(s，3H)。
Embodiment 107:6-chloro-9-(3,5-dimethoxy-4 '-methyl-benzyl)-9H-purine-2-base amine
Step 1:(3,5-dimethoxy-4 '-methyl-phenyl)-methyl alcohol
According to Bhaskar etc., J.Org.Chem.1991,56, the description reduction 3 among the 5964-5965,5-dimethoxy-4 '-methyl-phenylformic acid obtains title compound.HPLC?Rt：5.352min。 1H-NMR(CDCl 3)：δ6.58(s，2H)，4.68(s，2H)，3.85(s，6H)，2.10(s，3H)。
Step 2:5-brooethyl-1,3-dimethoxy-4 '-methyl-benzene
According to general step 2.5, obtain title compound by (3,5-dimethoxy-4 '-methyl-phenyl)-methyl alcohol.HPLC?Rt：7.200min。 1H-NMR(CDCl 3)：δ6.59(s，2H)，4.51(s，2H)，3.86(s，3H)，3.85(s，3H)，2.22(s，3H)。
Step 3:6-chloro-9-(3,5-dimethoxy-4 '-methyl-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 5-brooethyl-1,3-dimethoxy-4 '-methyl-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.841min。 1H-NMR(CDCl 3)：δ7.75(s，1H)，6.46(s，1H)，5.21(s，2H)，5.07(s，2H)，3.80(s，6H)，2.09(s，3H)。
Embodiment 108:9-(2-bromo-3,5-dimethoxy-4 '-methyl-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 3.1,6-chloro-9-(3,5-dimethoxy-4 '-methyl-benzyl)-6-chloro-9H-purine-2-base amine is carried out bromination, obtains title compound with bromine.HPLC?Rt：6.222min。 1H-NMR(CDCl 3)：δ7.85(s，1H)，6.60(s，1H)，5.36(s，2H)，5.07(s，2H)，3.80(s，3H)，3.74(s，3H)，2.20(s，3H)。
Embodiment 109:8-bromo-9-(2-bromo-3,5-dimethoxy-4 '-methyl-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 3.1,6-chloro-9-(3,5-dimethoxy-4 '-methyl-benzyl)-6-chloro-9H-purine-2-base amine is carried out bromination, obtains title compound with excessive bromine.HPLC?Rt：7.040min。 1H-NMR(CDCl 3)：δ5.88(s，1H)，5.38(s，2H)，5.14(s，2H)，3.83(s，3H)，3.57(s，3H)，2.19(s，3H)。
Embodiment 110:2,6-two chloro-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-lutidine (or its HCl salt) alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.081?min。 1H-NMR(CDCl 3)：δ8.30(s，1H)，8.17(s，1H)，5.50(s，2H)，3.80(s，3H)，2.38(s，3H)，2.27(s，3H)。
Embodiment 111:8-butyl-6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
Step 1:6-chloro-N4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4, the 5-triamine
By in butanols or ethanol with 4,6-two chloro-pyrimidines-2,5-diamines (referring to Seela etc., Helv.Chim.Acta.1986,69,1602-1613 and US patent No.5,917,042), 3,4,5-trimethoxy benzylamine and Et 3N backflow 1-14h obtains title compound.HPLC?Rt：4.327min。 1H-NMR(CDCl 3)：δ6.57(s，2H)，5.65(t，1H)，4.75(s，2H)，4.54(d，2H)，3.86-3.87(d，9H)。
Step 2:8-butyl-6-chloro-9-(3,4,5-trimethoxy-benzyl)-pyrimidine-2-base amine
Obtain title compound according to the step that provides among the WO 98/39344.HPLC?Rt：5.971min。 1H-NMR(CDCl 3)：δ6.34(s，2H)，5.19(s，2H)，5.04(s，2H)，3.81(s，3H)，3.77(s，6H)，2.71-2.75(t，2H)，1.68-1.74(m，2H)，1.35-1.41(m，2H)，0.88-0.92(t，2H)。
Embodiment 112:6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 3,4,5-trimethoxy benzyl alkylation 2-amino-6-chloropurine obtains title compound.Can also be at room temperature with 6-chloro-N-4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4 in the dense HCl processing triethyl orthoformate of catalytic amount, the 5-triamine solution obtained title compound in 20 minutes.HPLC?Rt：4.906min。 1H-NMR(CDCl 3)：δ7.76(s，1H)，6.51(s，2H)，5.18(s，2H)，5.12(s，2H)，3.85(s，3H)，3.84(s，6H)。
Embodiment 113: acetic acid 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenylester
Step 1: acetic acid 4-hydroxymethyl-2,6-dimethoxy-phenylester
Use NaBH under 0 ℃ 4(1 equivalent) handles the acetic acid 4-formyl radical-2 among the MeOH (100mL), 6-dimethoxy-phenylester (25mmol) solution 15 minutes.Behind acetone cancellation and evaporating solvent, handle (CH 2Cl 2) and evaporation, obtain title compound (productive rate 85%) into white solid.Rf (in EtOAc/ hexane 1: 1): 0.5. 1H-NMR(CDCl 3)：δ6.66(s，1H)，4.68-4.70(d，2H)，3.85(s，3H)，2.36(s，3H)，1.74(t，1H)。
Step 2: acetic acid 3-bromo-4-hydroxymethyl-2,6-dimethoxy-phenylester
According to general step 3.1, by tetrapropylammonium acetate 3-bromo-4-hydroxymethyl-2 in the AcOH/AcONa damping fluid, 6-dimethoxy-phenylester and obtain title compound.Rf (EtOAc/ hexane 1: 3): 0.2. 1H-NMR(CDCl 3)：δ7.01(s，1H)，4.75-4.76(d，2H)，3.86(s，3H)，3.85(s，3H)，2.38(s，3H)，2.05(t，1H)。
Step 3: acetic acid 3-bromo-4-brooethyl-2,6-dimethoxy-phenylester
According to general step 2.5, by acetic acid 3-bromo-4-hydroxymethyl-2,6-dimethoxy-phenylester obtains title compound.Rf (EtOAc/ hexane 1: 3): 0.8. 1H-NMR(CDCl 3)：δ6.87(s，1H)，4.60(s，2H)，3.84(s，3H)，3.83(s，3H)，2.36(s，3H)。
Step 4: acetic acid 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenylester
According to general step 1.1, with acetic acid 3-bromo-4-brooethyl-2,6-dimethoxy-phenylester alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.081min。 1H-NMR(CDCl 3)：δ8.30(s，1H)，8.17(s，1H)，5.50(s，2H)，3.80(s，3H)，2.38(s，3H)，2.27(s，3H)。
Embodiment 114:4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
Under the room temperature, at NH 3Dichlorodiphenyl Acetate 4-among the/MeOH (2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2; 6-dimethoxy-phenol (referring to embodiment before) carries out the deacetylated effect of 0.5h; perhaps in the K2CO3 of methyl alcohol solution, carry out deacetylatedly, obtain title compound according to general step 2.3.HPLC?Rt：4.912min。 1H-NMR(CDCl 3)：δ7.85(s，1H)，6.72(s，1H)，5.70(s，1H)，5.33(s，1H)，5.07(s，2H)，3.94(s，3H)，3.82(s，3H)。
Embodiment 115:9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 2.6, by to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (referring to embodiment before) carries out O-and methylates and obtain title compound.Can also be according to general step 3.1, by in the acetic ester damping fluid, 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine (referring to embodiment 48) being carried out bromination and obtains title compound.HPLC?Rt：5.742min。 1H-NMR(CDCl 3)：δ7.85(s，1H)，6.66(s，1H)，5.32(s，2H)，5.11(s，2H)，3.90(s，3H)，3.87(s，3H)，3.76(s，3H)。
Embodiment 116:9-(4-allyloxy-2 bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Exist down, use 3-bromo-propylene to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2 under 70 ℃ in DMF, 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.109min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，6.64(s，1H)，6.00-6.10(m，2H)，5.36-5.36(m，1H)，5.31(s，2H)，5.20-5.21(m，2H)，4.52-4.54(m，2H)，3.90(s，3H)，3.74(s，2H)。
Embodiment 117:9-(2-bromo-4-chlorine methoxyl group-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Exist down, under 70 ℃ in DMF with chloroiodomethane to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.109min。 1H-NMR(CDCl 3)：δ7.87(s，1H)，6.66(s，1H)，5.91(s，2H)，5.34(s，2H)，5.08(s，2H)，3.90(s，3H)，3.76(s，3H)。
Embodiment 118:9-[2-bromo-4-(2-chloro-oxyethyl group)-3,5-dimethoxy-benzyl]-6-chloro-9H-purine-2-base amine
At K 2CO 3Exist down, use 1-bromo-2-chloro-ethane to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2 under 70 ℃ in DMF, 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.285min。 1H-NMR(CDCl 3)：δ7.86(s，1H)，6.67(s，1H)，5.37(s，2H)，5.32(s，2H)，4.22-4.25(t，2H)，3.91(s，3H)，3.77-3.78(t，2H)3.75(s，3H)。
Embodiment 119:9-(2-bromo-4-cyclo propyl methoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Exist down, use brooethyl-cyclopropane to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2 under 70 ℃ in DMF, 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.512min。 1H-NMR(CDCl 3)：δ7.86(s，1H)，6.67(s，1H)，5.34(s，2H)，5.17(s，2H)，3.95(s，3H)，3.83-3.84(d，2H)，3.77(s，3H)1.27(m，1H)，0.58-0.62(m，2H)，0.28-0.32(m，2H)。
Embodiment 120:9-(2-bromo-4-oxyethyl group-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Existence is following, and the EtI under 70 ℃ among the usefulness DMF is to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2, and 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.112min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，6.65(s，1H)，5.31(s，2H)，5.13(s，2H)，4.04-4.09(q，2H)，3.90(s，3H)，3.82(s，3H)，1.32-1.38(t，3H)。
Embodiment 121:9-(2-bromo-3,5-dimethoxy-4 '-propoxy--benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Existence is following, and the PrI under 70 ℃ among the usefulness DMF is to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2, and 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.594min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，6.65(s，1H)，5.30(s，2H)，5.14(s，2H)，3.93-3.97(t，2H)，3.89(s，3H)，3.74(s，3H)，1.72-1.81(m，2H)，1.00-1.04(t，3H)。
Embodiment 122:9-(2-bromo-4-butoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
At K 2CO 3Existence is following, and the BuI under 70 ℃ among the usefulness DMF is to 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2, and 6-dimethoxy-phenol (referring to embodiment 50) carries out the alkylation of 0.25-1h, obtains title compound.HPLC?Rt：6.594min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，6.65(s，1H)，5.30(s，2H)，5.14(s，2H)，3.97-4.00(t，2H)，3.89(s，3H)，3.74(s，3H)，1.68-1.76(m，2H)，1.44-1.53(m，2H)，0.94-0.97(t，3H)。
Embodiment 123:6-chloro-9-(3-methoxymethoxy-6-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:(3-methoxymethoxy-6-methyl-pyridine-2-yl)-methyl alcohol
According to general step 2.6, use the chloromethyl methyl ether, O-alkylation 2-hydroxymethyl-6-methyl-pyridine-3-alcohol obtains title compound. 1H-NMR(CDCl 3)：δ7.28-7.30(d，1H)，6.98-7.00(d，1H)，5.17(s，2H)，4.71(s，2H)，4.50(s，2H)，3.45(s，3H)，2.49(s，3H)。
Step 2:2-brooethyl-3-methoxymethoxy-6-methyl-pyridine
According to general step 2.5, obtain title compound by (3-methoxymethoxy-6-methyl-pyridine-2-yl)-methyl alcohol. 1H-NMR(CDCl 3)：δ7.32-7.40(d?1H)，7.08-7.10(d，1H)，5.30(s，2H)，4.67(s，2H)，3.55(s，3H)，2.54(s，3H)。
Step 3:6-chloro-9-(3-methoxymethoxy-6-methyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-3-methoxymethoxy-6-methyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：3.884min。 1H-NMR(CDCl 3)：δ7.92(s，1H)，7.34-7.36(d，1H)，7.05-7.07(d，1H)，5.39(s，2H)，5.17(s，2H)，5.06(s，2H)，3.40(s，3H)，2.44(s，3H)。
Embodiment 124:3-(2-amino-6-chloro-purine-9-ylmethyl)-3H-benzothiazole-2-thioketones
According to general step 1.1,, obtain title compound with 3-chloromethyl-3H-benzothiazole-2-thioketones alkylation 2-amino-6-chloropurine.HPLC?Rt：5.982min。 1H-NMR(d 6-?DMSO)：δ8.37(s，1H)，8.25-8.28(d，1H)7.79-7.81(d，1H)，7.54-7.56(t，1H)，7.39-7.43(m?1H)，7.20(s，2H)，6.62(s，2H)，3.34(s，3H)。
Embodiment 125:6-chloro-9-(2,5-dimethyl-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloromethyl-1,4-dimethyl-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.920min。 1H-NMR(d 6-DMSO)：δ8.10(s，1H)，7.10(d，1H)7.04(d，1H)，6.95(s，2H)，6.65(s，1H)，5.23，(s，2H)，3.34(s，3H)，2.30(s，3H)，2.17(s，3H)。
Embodiment 126:6-chloro-9-isoquinolyl-1 methyl-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-isoquinoline 99.9, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.306min。 1H-NMR(d 6-DMSO)：δ8.43-8.45(d，1H)，8.27-8.28(d，1H)，8.20(s，1H)，8.03-8.05(d?1H)，7.85-7.89(m，1H)，7.77-7.82(m，2H)，6.83(s，2H)，6.04(s，2H)。
Embodiment 127:9-benzo [1,2,5]-thiadiazoles-5-ylmethyl-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 5-brooethyl-benzo [1,2,5] thiadiazoles, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.931min。 1H-NMR(d 6-DMSO)：δ8.31(s，1H)，8.11(d，1H)，7.87(br.s，1H)，7.70-7.67(dd，1H)，6.98(br，s，2H)，5.52(s，2H)。
Embodiment 128:9-(1-methyl isophthalic acid H-benzotriazole-5-ylmethyl)-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 6-brooethyl-1-methyl-benzotriazole, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.295min。 1H-NMR(d 6-DMSO)：δ8.29(s，1H)，7.95(s，1H)，7.86-7.84(d，1H)，7.55-7.53(dd，1H)，6.97(s，2H)，5.45(s，2H)，4.3(s，3H)。
Embodiment 129:6-chloro-9-(6-chloro-benzo [1,2,5]-thiadiazoles-5-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 5-brooethyl-6 chloro--benzo [1,2,5] thiadiazoles, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.400min。 1H-NMR(d 6-DMSO)：δ8.45(s，1H)，8.20(s，1H)，7.64(s，1H)，6.97(s，2H)，5.55(s，2H)。
Embodiment 130:9-benzo [1,2,5]-thiadiazoles-4-ylmethyl-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 4-brooethyl-benzo [1,2,5] thiadiazoles, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.027min。 1H-NMR(d 6-DMSO)：δ8.26(s，1H)，8.04-8.07(d，1H)，7.68-7.64(dd，1H)，7.22-7.20(dd，1H)，6.93(s，2H)，5.79(s，2H)。
Embodiment 131:6-chloro-9-(6-fluoro-4a, 8a-dihydro-4H-benzo [1,3] dioxin-8-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 8-chloromethyl-6-fluoro-4a, 8a-dihydro-4H-benzo [1,3] dioxin alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.172min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，6.92-6.89(dd，1H)，6.70-6.67(dd，1H)，5.31(s，2H)，5.22(s，2H)，5.07(s，2H)，4.90(s，2H)。
Embodiment 132:1-[3-(2-amino-6-chloro-purine-9-ylmethyl)-4-methoxyl group-phenyl] ethyl ketone
According to general step 1.1,, obtain title compound with 1-(3-chloromethyl-4-methoxyl group-phenyl)-ethyl ketone alkylation alkylation 2-amino-6-chloropurine.HPLC?Rt：4.887min。 1H-NMR(CDCl 3)：δ8.03-8.02(d，1H)，7.97-7.95(dd，1H)，7.81(s，1H)，6.96-6.93(d，1H)，5.25(s，2H)，5.08(s，2H)，3.93(s，3H)，2.54(s，3H)。
Embodiment 133:6-chloro-9-(3-trifluoromethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-chloromethyl-3-trifluoromethoxy-benzene, alkylation alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.965min。 1H-NMR?(CDCl 3)：δ7.76(s，1H)，7.39-7.37(t，1H)，7.21-7.15(m，3H)，5.27(s，2H)，5.12(s，2H)。
Embodiment 134:6-chloro-9-(2-fluoro-3-trifluoromethyl-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-fluoro-3-trifluoromethyl-benzene, alkylation alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.841min。 1H-NMR(CDCl 3)：δ7.83(s，1H)，7.63-7.59(t，1H)，7.48-7.45(t，1H)，7.25-7.22(t，1H)，5.36(s，2H)，5.12(s，2H)。
Embodiment 135:6-chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:(2-fluoro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
Under 0-23 ℃, use NaBH 4(1.2 equivalent) to the 2-fluoro-4 among the MeOH (10mL), 5-dimethoxy-benzaldehyde solution carries out the processing of 0.5h.Behind acetone cancellation and evaporating solvent, treated (CH 2Cl 2), dry (MgSO 4) and evaporation, obtain title compound (productive rate 94%) into thick oily product. 1H-NMR(CDCl 3)：δ6.90-6.88(d，1H)，6.61-6.64(d，1H)，4.65-4.63(d，2H)，3.86(s，3H)，3.84(s，3H)，2.00-1.94(t，1H)。
Step 2:1-brooethyl-2-fluoro-4,5-dimethoxy-benzene
According to general step 2.5, obtain title compound by (2-fluoro-4,5-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ6.84-6.81(d，1H)，6.64-6.61(d，1H)，4.52(s，2H)，3.89(s，3H)，3.84(s，3H)。
Step 3:6-chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-fluoro-4,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.939min。 1H-NMR(CDCl 3)：δ7.79(s，1H)，6.88-6.85(d，1H)，6.69-6.66(d，1H)，5.22(s，2H)，5.12(s，2H)，3.89(s，3H)，3.82(s，3H)。
Embodiment 136:6-chloro-9-(2,3-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:1-brooethyl-2,3-dimethoxy-benzene
According to general step 2.5, obtain title compound by (2,3-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ7.02-7.08(t，1H)，6.95-6.98(dd，1H)，6.87-6.91(dd，1H)，4.57(s，2H)，3.92(s，3H)，3.86(s，3H)。
Step 2:6-chloro-9-(2,3-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2,3-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.200min。 1H-NMR(CDCl 3)：δ7.81(s，1H)，7.02-7.08(t，1H)，6.95-6.98(dd，1H)，6.87-6.91(dd，1H)，5.28(s，2H)，5.12(s，2H)，3.92(s，3H)，3.87(s，3H)。
Embodiment 137:6-chloro-9-(3,4-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:4-brooethyl-1,2-dimethoxy-benzene
According to general step 2.5, obtain title compound by (3,4-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ6.95-6.98(dd，1H)，6.92-6.94(d，1H)，6.78-6.81(d，1H)，4.51(s，2H)，3.92(s，3H)，3.86(s，3H)。
Step 2:6-chloro-9-(3,4-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 4-brooethyl-1,2-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.753min。
1H-NMR(CDCl 3)：δ7.71(s，1H)，6.87(s，2H)，6.82(s，1H)，5.20(s，2H)，5.12(s，2H)，3.92(s，3H)，3.87(s，3H).
Embodiment 138:9-(2-chloro-3,4,5-trimethoxy-benzyl)-6-methyl-9H-purine-2-base amine
Under nitrogen, with trimethyl aluminium (the 2M solution in the toluene, 0.45mmol) processing 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine (closes solution and the reflux 3h that palladium (0.02mmol) forms referring to embodiment 97 (0.2mmol) and four (triphenylphosphinyls) in exsiccant THF (3mL).Reaction mixture is cooled to room temperature, with toluene (5mL) dilution and with methyl alcohol (0.5mL) and ammonium chloride subsequently (1mmol) cancellation.With mixture heating up reflux 2h and on diatomite filtered while hot.Referring to J.Med.Chem.1999,42,2064-2086.TLC (100%EtOAc) Rf is 0.2.HPLC?Rt：4.800min。
Embodiment 139:6-chloro-9-(2-chloro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:(2-chloro-4,5-dimethoxy-phenyl) methyl alcohol
According to general step 3.1, the chlorization by (3,4-dimethoxy-phenyl)-methyl alcohol obtains title compound. 1H-NMR(CDCl 3)：δ7.01(s，1H)，6.88(s，1H)，4.75-4.73(d，2H)，3.91(s，3H)，3.90(s，3H)，1.95-1.92(t，1H)。
Step 2:1-brooethyl-2-chloro-4,5-dimethoxy-benzene
According to general step 2.5, obtain title compound by (2-chloro-4,5-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ6.92(s，1H)，6.88(s，1H)，4.60(s，2H)，3.91(s，3H)，3.90(s，3H)。
Step 3:6-chloro-9-(2-chloro-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-chloro-4,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.366min。 1H-NMR(CDCl 3)：δ7.81(s，1H)，7.28(s，1H)，6.92(s，1H)，5.30(s，2H)，5.15(s，2H)，3.90(s，3H)，3.84(s，3H)。
Embodiment 140:6-chloro-9-(2-iodo-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:4-brooethyl-1,2-dimethoxy-benzene
According to general step 2.5, obtain title compound by (3,4-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ6.95-6.98(dd，1H)，6.92-6.94(d，1H)，6.78-6.81(d，1H)，4.51(s，2H)，3.92(s，3H)，3.86(s，3H)。
Step 2:1-brooethyl-2-iodo-4,5-dimethoxy-benzene
According to general step 3.1, by 4-brooethyl-1, the iodization of 2-dimethoxy-benzene obtains title compound. 1H-NMR(CDCl 3)：δ7.04(s，1H)，6.95(s，1H)，4.61(s，2H)，3.91(s，3H)，3.90(s，3H)。
Step 3:6-chloro-9-(2-iodo-4,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-iodo-4,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.470min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，7.08(s，1H)，6.93(s，1H)，5.30(s，2H)，5.15(s，2H)，3.91(s，3H)，3.82(s，3H)。
Embodiment 141:6-bromo-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
Step 1:2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
According to general step 3.1, by 5-chloromethyl-1,2, the chlorization of 3-trimethoxy-benzene obtains title compound. 1H-NMR(CDCl 3)：δ6.82(s，1H)，4.70(s，1H)，3.93(s，3H)，3.90(s，3H)3.87(s，3H)。
Synthesizing of step 2:6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene, alkylation 6-bromine guanine obtains title compound.HPLC?Rt：5.676min。 1H-NMR(CDCl 3)：δ7.82(s，1H)，6.70(s，1H)，5.32(s，2H)，5.15(s，2H)，3.93(s，3H)，3.91(s，3H)3.79(s，3H)。
Embodiment 142:6-chloro-9-(6-chloro-benzo [1,3] dioxole-5-ylmethyl)-9H-purine-2-base amine
According to general step 1.1,, obtain title compound with 5-chloro-6-chloromethyl-benzo [1,3] dioxole alkylation 2-amino-6-chloropurine.HPLC?Rt：5.506min。 1H-NMR(CDCl 3)：δ7.81(s，1H)，6.88(s，1H)，6.79(s，1H)，5.98(s，2H)，5.25(s，2H)，5.13(s，2H)。
Embodiment 143:6-chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purine-2-base amine
Step 1:1-brooethyl-2,4-dimethoxy-3-methyl-benzene
According to general step 2.5, obtain title compound by (2,4-dimethoxy-3-methyl-phenyl)-methyl alcohol.
Step 2:6-chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2,4-dimethoxy-3-methyl-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.433min。 1H-NMR(CDCl 3)：δ7.76(s，1H)，7.08-7.06(d，1H)，6.60-6.62(d，1H)，5.20(s，2H)，5.07(s，2H)，3.82(s，3H)，3.72(s，3H)，2.17(s，3H)。
Embodiment 144:6-chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:1-brooethyl-2-chloro-3,4-dimethoxy-benzene
According to general step 2.5, obtain title compound by (2-chloro-3,4-dimethoxy-phenyl)-methyl alcohol.
Step 2:6-chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-chloro-3,4-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.633min。 1H-NMR(CDCl 3)：δ7.80(s，1H)，7.00-6.98(d，1H)，6.82-6.79(d，1H)，5.31(s，2H)，5.08(s，2H)，3.88(s，3H)，3.88(s，3H)。
Embodiment 145:6-chloro-9-(3-methoxyl group-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-3-anisole, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.136min。 1H-NMR(CDCl 3)：δ7.75(s，1H)，7.30-7.28(m.1H)，6.88-6.85(dd，1H)，6.84-6.82(dd，1H)，6.80-6.79(m，1H)，5.28(s，2H)，5.15(s，2H)，3.78(s，3H)。
Embodiment 146:6-chloro-9-(2,6-two bromo-3,5-dimethoxy-benzyl)-9H-purine-2-base amine
Step 1:2-bromo-1-chloromethyl-3,5-dimethoxy-benzene and 2,4-two bromo-3-chloromethyls-1,5-dimethoxy-benzene
According to 3.1 pairs of 1-chloromethyls-3 of general step, 5-dimethoxy-benzene carries out the mixture that bromination obtains two kinds of title compounds, by flash chromatography it is separated.2,4-two bromo-3-chloromethyls-1,5-dimethoxy-benzene 1HMR (CDCl 3): δ 6.52 (s, 1H), 5.02 (s, 2H), 3.93 (s, 6H).2-bromo-1-chloromethyl-3,5-dimethoxy-benzene 1HMR (CDCl 3): δ 6.67-6.67 (d, 1H), 6.47-6.46 (d, 1H), 4.80 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H).
Step 2:6-chloro-9-(2,6-two bromo-3,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 2,4-two bromo-3-chloromethyls-1,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：6.022min。 1H-NMR(CDCl 3)：δ7.46(s，1H)，6.64(s，1H)，5.64(s，2H)，5.14(s，2H)，3.99(s，?6H)。
Embodiment 147:9-(2-bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 2-bromo-1-chloromethyl-3,5-dimethoxy-benzene, (referring to embodiment before, step 1) obtains title compound to alkylation 2-amino-6-chloropurine.HPLCRt：6.026min。 1H-NMR(CDCl 3)：δ7.82(s，1H)，6.48-6.47(d，1H)，6.32-6.32(d，1H)，5.35(s，2H)，5.09(s，2H)，3.90(s，3H)，3.73(s，3H)。
Embodiment 148:6-chloro-9-(3,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-chloromethyl-3,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.257min。 1H-NMR(CDCl 3)：δ7.79(s，1H)，6.44-6.42(t，1H)，6.41-6.39(d，2H)，5.22(s，2H)，5.15(s，2H)，3.80(s，6H)。
Embodiment 149:N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-yl]-ethanamide
Under 0 ℃, with the HNO of being fuming 36-chloro-9-in the Dichlorodiphenyl Acetate (3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine aqueous solution carries out handling in 15 minutes.Handle and through preparation property TLC (EtOAc: hexane 1: 1) obtain N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-yl]-ethanamide.HPLC?Rt：5.744min。 1H-NMR(CDCl 3)：δ8.09(s，1H)，6.58(s，2H)，5.33(s，2H)，3.85(s，3H)，3.85(s，6H)，2.43(s，3H)。
Embodiment 150:6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-chloromethyl-2,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.291min。 1H-NMR(CDCl 3)：δ7.82(s，1H)，6.85-6.84(d，1H)，6.82-6.82(d，2H)，5.18(s，2H)，5.16(s，2H)，3.80(s，3H)，3.75(s，3H)。
Embodiment 151:8-bromo-6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.2, by the bromination acquisition title compound of 6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purine-2-base amine.HPLC?Rt：6.150min。 1H-NMR(CDCl 3)：δ6.83-6.78(m，2H)，6.37-6.36(d，1H)，5.31(s，2H)，5.13(s，2H)，3.83(s，3H)，3.70(s，3H)。
Embodiment 152:6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-4,5-dimethoxy-2-nitro-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.194min。 1H-NMR(CDCl 3)：δ7.98(s，1H)，7.74(s，1H)，6.79(s，1H)，5.67(s，2H)，5.15(s，2H)，3.98(s，3H)，3.85(s，3H)。
Embodiment 153:8-bromo-6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purine-2-base amine
According to general step 1.2, by the bromination acquisition title compound (referring to embodiment before) of 6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purine-2-base amine.HPLCRt：6.040min。 1H-NMR(CDCl 3)：δ7.74(s，1H)，6.13(s，1H)，5.78(s，2H)，5.16(s，2H)，3.99(s，3H)，3.71(s，3H)。
Embodiment 154:6-chloro-9-(2,5-two chloro-benzyls)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-1,4-two chloro-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.846min。 1H-NMR(CDCl 3)：δ7.82(s，1H)，7.38-7.36(d，1H)，7.28-7.26(dd，1H)，7.18-7.18(d，1H)，5.32(s，2H)，5.17(s，2H)。
Embodiment 155:6-chloro-9-(2,3,5-three fluoro-benzyls)-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2,3,5-three fluoro-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.414min。 1H-NMR(CDCl 3)：δ7.82(s，1H)，6.98-6.89(m，1H)，6.82-6.75(m，1H)，5.30(s，2H)，5.13(s，2H)。
Embodiment 156:(2-amino-6-chloro-purine-9-yl)-(3,4,5-trimethoxy-phenyl)-ketone
With 3,4, the 5-trimethoxy-benzoyl chloride is handled 6-chloro-9H-purine-solution of 2-base amine in pyridine carries out 2h under the room temperature.Handle and (EtOAc: hexane 1: 1) purifying obtains title compound through preparation TLC.HPLC?Rt：5.305min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，7.13(s，2H)，5.36(s，2H)，3.99(s，3H)，3.88(s，6H)。
Embodiment 157:N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-yl]-ethanamide
Use the dense H of catalytic amount under the room temperature 2SO 49-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-suspension of 2-base amine (embodiment 51) in acetic anhydride is carried out the processing of 3h.Handle and (EtOAc: hexane 9: 1) purifying obtains title compound through preparation TLC.HPLCRt：5.603min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，8.10(s，1H)，7.00(s，1H)，5.47(s，2H)，3.92(s，3H)，3.90(s，3H)，3.86(s，3H)，2.51(s，3H)。
Embodiment 158:N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-yl]-N-methyl-ethanamide
Under the room temperature with N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-2-yl]-ethanamide and the NaH mixture in DMF stirred 15 minutes, added Mel then.Continue to stir 2h in 50 ℃.Handle and (EtOAc: hexane 9: 1) purifying obtains title compound through preparation TLC.HPLC?Rt：5.603min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，6.80(s，1H)，5.45(s，2H)，3.93(s，3H)，3.90(s，3H)，3.82(s，3H)，3.57(s，3H)，2.51(s，3H)。
Embodiment 159:6-chloro-9-(3,5-two chloro-benzyls)-9H-purine-2-base amine
Step 1:1-brooethyl-3,5-two chloro-benzene
According to general step 2.5, obtain title compound by (3,5-two chloro-phenyl)-methyl alcohol.
Step 2:6-chloro-9-(3,5-two chloro-benzyls)-9H-purine-2-base amine
With 1-brooethyl-3,5-two chloro-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：6.074min。 1H-NMR (acetone-d6): δ 8.12 (s, 1H), 7.45-7.43 (t, 1H), 7.72-7.42 (d, 2H), 6.30 (s, 2H), 5.40 (s, 2H).
Embodiment 160:6-chloro-9-(3,4-two chloro-benzyls)-9H-purine-2-base amine
According to general step 1.1, with 4-brooethyl-1,2-two chloro-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.982min。 1H-NMR(CDCl 3)：δ7.76(s，1H)，7.48-7.45(d，1H)，7.40-7.39(d，1H)，7.12-7.10(dd，1H)，5.23(s，2H)，5.12(s，2H)。
Embodiment 161:8-bromo-6-chloro-9-(3,4-two chloro-benzyls)-9H-purine-2-base amine
According to general step 1.2, the bromination by 6-chloro-9-(3,4-two chloro-benzyls)-9H-purine-2-base amine obtains title compound (referring to embodiment before).HPLC?Rt：6.878min。 1H-NMR(CDCl 3)：δ7.45-7.43(m，2H)，7.17-7.14(dd，1H)，5.23(s，2H)，5.12(s，2H)。
Embodiment 162:6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
Carry out chlorination according to 3.1 pairs of 6-chloro-of general step 9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine, obtain the mixture of title compound and 6-chloro-9-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine.TLC separates two compounds by preparation property.HPLCRt：5.626min。 1H-NMR(CDCl 3)：δ7.83(s，1H)，6.68(s，1H)，5.51(s，2H)，5.23(s，2H)，3.94(s，3H)，3.90(s，3H)，3.80(s，3H)。
Embodiment 163:6-chloro-9-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
Referring to embodiment before.HPLC?Rt：6.099min。 1H-NMR(CDCl 3)：δ7.57(s，1H)，5.48(s，2H)，5.12(s，2H)，3.99(s，3H)，3.92(s，6H)。
Embodiment 164:2-amino-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-6-alcohol
By the 6-chloro-9-among the 1N HCl (2-chloro-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine aqueous solution heating 4h is obtained title compound (referring to embodiment 98).Evaporating solvent also washs residuum with EtOAc, obtains title compound.HPLC?Rt：4.603min。 1H-NMR(DMSO-d6)：δ7.82(s，1H)，6.65(s，1H)，6.60(s，2H)，5.15(s，2H)，3.81(s，3H)，3.77(s，3H)，3.69(s，3H)。
Embodiment 165:6-bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 3-chloromethyl-3,4,5-trimethoxy-benzene, alkylation 6-bromine guanine obtains title compound.HPLC?Rt：4.947min。 1H-NMR(CDCl 3)：δ7.80(s，1H)，6.50(s，2H)，5.20(s，2H)，5.18(s，2H)，3.85(s，3H)，3.84(s，6H)。
Embodiment 166:6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
According to general step 3.1, the bromination by 6-bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine obtains title compound (embodiment before participating in).HPLC?Rt：5.793min。 1H-NMR(CDCl 3)：δ7.88(s，1H)，6.68(s，1H)，5.33(s，2H)，5.19(s，2H)，3.93(s，3H)，3.90(s，3H)，3.79(s，3H)。
Embodiment 167:9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-ethyl sulfane base-9H-purine-2-base amine
The mixture of 6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine (referring to embodiment before), EtSH, K2CO3 and THF is placed in the autoclave and is heated to 70 ℃ keep 6h.Handle and (EtOAc: hexane 1: 1) purifying obtains title compound through preparation property TLC.HPLC?Rt：6.039min。 1H-NMR(CDCl 3)：δ7.72(s，1H)，6.62(s，1H)，5.30(s，2H)，4.98(s，2H)，3.91(s，3H)，3.88(s，3H)，3.74(s，3H)，3.35-3.29(q，2H)，1.44-1.41(t，3H)。
Embodiment 168:9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxyl group-9H-purine-2-base amine
Under refluxing with MeONa with 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-solution-treated 1h of 2-base amine (referring to embodiment 51) in MeOH.Handle and (EtOAc: hexane 1: 1) purifying obtains title compound through preparation property TLC.HPLC?Rt：5.229min。 1H-NMR(CDCl 3)：δ7.69(s，1H)，6.58(s，1H)，5.33(s，2H)，4.88(s，2H)，4.11(s，3H)，3.93(s，3H)，3.89(s，3H)，3.74(s，3H)。
Embodiment 169:9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2, the 6-diamines
Under 90 ℃, in autoclave, use NH 3(the 7N solution among the MeOH) carries out the processing of 16h to 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purine-solution of 2-base amine in MeOH.Handle and (EtOAc: hexane 3: 1) purifying obtains title compound through preparation property TLC.HPLC?Rt：4.884min。 1H-NMR(CDCl 3)：δ7.67(s，1H)，6.71(s，2H)，6.60(s，1H)，5.84(s，2H)，5.17(s，2H)，3.80(s，3H)，3.76(s，3H)，3.66(s，3H)。
Embodiment 170:6-chloro-9-(2-iodo-3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine
According to general step 3.1, the iodate by 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine-2-base amine (referring to embodiment 48) obtains title compound.HPLC?Rt：5.887min。 1H-NMR(CDCl 3)：δ7.87(s，1H)，6.67(s，1H)，5.33(s，2H)，5.22(s，2H)，3.91(s，3H)，3.88(s，3H)，3.77(s，3H)。
Embodiment 171:9-(2-bromo-3,5-dimethoxy-4 '-methoxymethoxy-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 2.6 (under the room temperature, NaOH, THF), by using chloromethyl methyl ether alkylation 4-(2-amino-6-chloro-purine-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (referring to embodiment 50) obtains title compound.HPLC?Rt：5.817min。 1H-NMR(CDCl 3)：δ7.90(s，1H)，6.70(s，1H)，5.35(s，2H)，5.32(s，2H)，5.17(s，2H)，3.93(s，3H)，3.78(s，3H)，3.62(s，3H)。
Embodiment 172:9-benzothiazole-2-ylmethyl-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-benzothiazole, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.055min。 1H-NMR(CDCl 3)：δ8.34(s，1H)，8.09-8.07(dd，1H)，7.98-7.96(d，1H)，7.53-7.50(m，1H)，7.47-7.43?(m，1H)，7.01(s，2H)，5.81(s，2H)。
Embodiment 173:6-chloro-9-(4-methoxyl group-benzyl)-9H-purine-2-base amine
According to general step 1.1, with 1-chloromethyl-4-methoxyl group-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.067min。 1H-NMR(CDCl 3)：δ7.69(s，1H)，7.22-7.20(d，2H)，6.88-6.86(d，2H)，5.22(s，2H)，5.17(s，2H)，3.79(s，3H)。
Embodiment 174:9-(2-bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
Step 1:(2-bromo-4,5-dimethoxy-phenyl)-methyl alcohol
According to general step 3.1, the bromination by (3,4-dimethoxy-phenyl)-methyl alcohol obtains title compound. 1H-NMR(CDCl 3)：δ7.03(s，1H)，7.03(s，1H)，4.70(s，2H)，3.91(s，3H)，3.89(s，3H)。
Step 2:1-brooethyl-2-chloro-4,5-dimethoxy-benzene
According to general step 2.5, obtain title compound by (2-bromo-4,5-dimethoxy-phenyl)-methyl alcohol. 1H-NMR(CDCl 3)：δ7.03(s，1H)，6.94(s，1H)，4.60(s，2H)，3.89(s，3H)，3.86(s，3H)。
Step 3:9-(2-bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purine-2-base amine
According to general step 1.1, with 1-brooethyl-2-chloro-4,5-dimethoxy-benzene, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.458min。 1H-NMR(CDCl 3)：δ7.84(s，1H)，7.08(s，1H)，6.93(s，1H)，5.30(s，2H)，5.15(s，2H)，3.90(s，3H)，3.82(s，3H)。
Embodiment 175:6-chloro-9-(4-iodo-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:2,3,5-collidine-N-oxide compound
According to general step 2.1, by 2,3, the oxidation of 5-collidine obtains title compound (productive rate 70%).HPLC?Rt：3.964min。 1H-NMR(CDCl 3)：δ8.03(s，1H)，6.90(s，1H)，2.47(s，3H)，2.31(s，3H)，2.24(s，3H)。m/z(％)138.2(M+1，?100％)。Rf (20%MeOH/EtOAc) is 0.35.
Step 2:2,3,5-trimethylammonium-4-nitro-pyridine 1-oxide compound
With 2,3, (3.77g is 28mmol) at dense H for 5-collidine-N-oxide compound 2SO 4Suspension (8mL) is cooled to 0 ℃ and also drips the HNO of being fuming 3(5mL, 100mmol).100 ℃ of clear solution 24h that stir down gained are cooled to room temperature, are poured on ice and with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain title compound (productive rate 97, purity 97%).Rf(MeOH/EtOAc?1∶9)：0.7。HPLC?Rt：4.756min。 1H-NMR(CDCl 3)：δ8.08(s，1H)，2.50(s，3H)，2.27(s，3H)，2.23(s，3H)。m/z(％)183.1(M+1，100％)。
Step 3:2,3,5-trimethylammonium-pyridin-4-yl amine-1-oxide hydrochloride
Use H under the room temperature 2(60psi) handle 2,3, and 5-trimethylammonium-4-nitro-pyridine 1-oxide compound (4.2g, 23mmol) and the suspension 3h of 10%Pd/C (0.42g) in dense HCl/EtOH (1: the 11) aqueous solution.Filtration and evaporation obtain the title compound into light yellow solid.HPLCRt：4.756min。 1H-NMR(DMSO-d 6)：δ8.28(s，1H)，7.24(s，2H)，2.50(s，3H)，2.12(s，3H)，2.11(s，3H)。m/z(％)153.2(M+1，100％)。
Step 4:4-iodo-2,3,5-trimethylammonium-pyridine-1-oxide compound
With 2,3, and 5-trimethylammonium-pyridin-4-yl amine-1-oxide hydrochloride (1.9g, 10mmol) and HBF 4(20mmol) solution in water (50mL) is cooled to 0 ℃.Drip NaNO 2(0.76g, 11mmol) solution in water (5mL) obtains deep yellow solution, forms throw out gradually in its 15 minutes.Divide some parts slowly to add potassiumiodide (2.3g, 1.39 * 10 -2Mol) to obtain coffee-like throw out.At room temperature stirred reaction mixture is 5 minutes, is heated to 60 ℃ then and keeps 10 minutes.Mixture is cooled to room temperature and with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4), evaporation, and obtain title compound through flash chromatography.HPLC?Rt：5.579min。 1H-NMR(CDCl 3)：δ8.07(s，1H)，2.62(s，3H)，2.56(s，3H)，2.38(s，3H)。m/z(％)264.1(M+1，100％)。
Step 5: acetic acid 4-iodo-3,5-dimethyl-pyridine-2-base methyl esters
According to general step 2.2, use Ac 2O handles 4-iodo-3, and 5-dimethyl-pyridine 1-oxide compound obtains title compound.HPLC?Rt：2.913min。 1H-NMR(CDCl 3)：δ8.26(s，1H)，5.32(s，2H)，2.47(s，3H)，2.41(s，3H)，2.24(s，3H)。m/z(％)306.0(M+1，?100％)。
Step 6:(4-iodo-3,5-dimethyl-pyridine-2-yl)-methyl alcohol
According to general step 2.3, by 4-iodo-3, the deacetylation of 5-dimethyl-pyridine-2-base methyl esters obtains title compound.HPLC?Rt：3.773min。 1H-NMR(CDCl 3)：δ8.15(s，1H)，4.70(s，2H)，2.46(s，3H)，2.40(s，3H)。m/z(％)264.1(M+1，100％)。
Step 7:2-brooethyl-4-iodo-3,5-dimethyl-pyridine
According to general step 2.5, obtain title compound by (4-iodo-3,5-dimethyl-pyridine-2-yl)-methyl alcohol.HPLC?Rt：5.957min。 1H-NMR(CDCl 3)：δ8.14(s，1H)，4.67(s，2H)，2.59(s，3H)，2.45(s，3H)。m/z(％)326.07(M+1，100％)，328.07(M+1，100％)。
Step 8:6-chloro-9-(4-iodo-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-4-iodo-3,5-dimethyl-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：5.361min。 1H-NMR(CDCl 3)：δ8.08(s，1H)，7.86(s，1H)，5.41(s，2H)，5.04(s，2H)，2.57(s，3H)，2.41(s，3H)。
Embodiment 176:6-chloro-9-(4-methyl-quinoline-2-ylmethyl)-9H-purine-2-base amine
Step 1:2,4-diformazan yl-quinoline 1-oxide compound:
According to general step 2.1, by 2, the oxidation of 4-diformazan yl-quinoline obtains title compound.HPLC?Rt：4.489min。 1H-NMR(CDCl 3)：δ8.89-8.07(dd，1H)，8.00-7.97(dd，1H)，7.82-7.79(m，1H)，7.69-7.65(m，1H)，7.20(s，1H)，2.73(s，3H)，2.69(s，3H)。
Step 2: acetic acid 4-methyl-quinoline-2-base methyl esters
According to general step 2.2, use Ac 2O handles 2, and 4-diformazan yl-quinoline 1-oxide compound obtains title compound.HPLC?Rt：3.158min。Rf (EtOAc/ hexane 1: 1): 0.8.
Step 3:(4-methyl-quinoline-2-yl)-methyl alcohol
According to general step 2.3, the deacetylation by acetic acid 4-methyl-quinoline-2-base methyl esters obtains title compound.HPLC?Rt：3.715min。 1H-NMR(CDCl 3)：δ8.08-8.06?(dd，1H)，8.00-7.97(dd，1H)，7.73-7.69(m，1H)，7.57-7.54(m，1H)，7.12(s，1H)，4.87(s，2H)，4.52(s，1H)，2.70(s，3H)。
Step 4:2-brooethyl-4-methyl-quinoline:
According to general step 2.5, obtain title compound by (4-methyl-quinoline-2-yl)-methyl alcohol.HPLC?Rt：4.516min。 1H-NMR(CDCl 3)：δ8.07-8.05(dd，1H)，7.98-7.96(dd，1H)，7.73-7.69(m，1H)，7.58-7.54(m，1H)，7.40(d，1H)，4.66(s，2H)，2.70(s，3H)。
Step 5:6-chloro-9-(4-methyl-quinoline-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1, with 2-brooethyl-4-methyl-quinoline, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.387min。 1H-NMR(DMSO-d6)：δ8.31(s，1H)，8.11-8.09(dd，1H)，7.90-7.88(dd，1H)，7.77-7.74(m，1H)，7.66-7.62(m，1H)，7.27(s，1H)，6.91(s，2H)5.58(s，2H)，2.68(s，3H)。
Embodiment 177:6-bromo-9-(4-methyl-quinoline-2-ylmethyl)-9H-purine-2-base amine
According to general step 1.1,, obtain title compound with 2-brooethyl-4-methyl-quinoline (referring to embodiment before) alkylation 6-bromine guanine.HPLC?Rt：4.489min。 1H-NMR(DMSO-d 6)：δ8.27(s，1H)，8.06-8.04(dd，1H)，7.85-7.83(dd，1H)，7.73-7.69(m，1H)，7.61-7.57(m，1H)，7.22(s，1H)，6.89(s，2H)，5.52(s，2H)，2.64(s，3H)。
Embodiment 178:6-bromo-9-(4-methyl isophthalic acid-oxygen-quinoline-2-ylmethyl)-9H-purine-2-base amine
According to general step 2.1, the oxidation by 6-bromo-9-(4-methyl-quinoline-2-ylmethyl)-9H-purine-2-base amine obtains title compound (referring to embodiment before).HPLC?Rt：4.698min。 1H-NMR(DMSO-d 6)：δ8.62-8.60(dd，1H)，8.27(s，1H)，8.12-8.10(dd，1H)，7.88-7.85(m，1H)，7.79-7.75(m，1H)，6.93(s，2H)，6.89(s，1H)5.57(s，2H)，2.64(s，3H)。
Embodiment 179:6-chloro-9-(3,5-dimethyl-4-methyl sulfane base-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:2,3,5-trimethylammonium-4-methyl sulfane base-pyridine 1-oxide compound
In autoclave, handle 4-bromo-2,3, the 5-trimethylammonium-solution 16h of pyridine 1-oxide compound in THF under 110 ℃ with NaSMe.HPLC?Rt：5.303min。 1H-NMR(CDCl 3)：δ8.07(s，1H)，2.57(s，3H)，2.52(s，3H)，2.42(s，3H)，2.23(s，3H)。
Step 2: acetic acid 3,5-dimethyl-4-methyl sulfane base-pyridine-2-base methyl esters
According to general step 2.2, use Ac 2O handles 2,3, and 5-trimethylammonium-4-methyl sulfane base-pyridine 1-oxide compound obtains title compound.HPLC?Rt：4.341min。 1H-NMR(CDCl 3)：δ8.27(s，1H)，5.20(s，2H)，2.57(s，3H)，2.46(s，3H)，2.25(s，3H)，2.10(s，3H)。
Step 3:(3,5-dimethyl-4-methyl sulfane base-pyridine-2-yl)-methyl alcohol:
According to general step 2.3, by acetic acid 3, the deacetylation of 5-dimethyl-4-methyl sulfane base-pyridine-2-base methyl esters obtains title compound.HPLC?Rt：3.921min。
Step 4:2-brooethyl-3,5-dimethyl-4-methyl sulfane base-pyridine
According to general step 2.5, obtain title compound by (3,5-dimethyl-4-methyl sulfane base-pyridine-2-yl)-methyl alcohol.HPLC?Rt：4.905min。 1H-NMR(CDCl 3)：δ8.26(s，1H)，4.59(s，2H)，2.62(s，3H)，2.47(s，3H)，2.27(s，3H)，2.10(s，3H)。m/z(％)：246.13(M+1，96％)，248.09(M+3，100％)。
Step 5:6-chloro-9-(3,5-dimethyl-4-methyl sulfane base-pyridine-2-ylmethyl)-basic amine of 9H-purine-2
According to general step 1.1, with 2-brooethyl-3,5-dimethyl-4-methyl sulfane base-pyridine, alkylation 2-amino-6-chloropurine obtains title compound.HPLC?Rt：4.611min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，7.87(s，1H)，5.36(s，2H)，5.00(s，2H)，2.61(s，3H)，2.47(s，3H)，2.26(s，3H)。
Embodiment 180:6-chloro-9-(7-chloro-benzothiazole-2-ylmethyl)-9H-purine-2-base amine
Step 1:(2,3-two chloro-phenyl)-ethanamide
With 2, (5.00g, 30.86mmol) solution in pyridine (20mL) is cooled to 0 ℃ to the 3-dichlorphenamide bulk powder, and (4.85g 62mmol) handles with AcCl.Stirred reaction mixture 1h, concentrating under reduced pressure then under the room temperature.Residuum is dissolved in the vinyl acetic monomer, the aqueous hydrochloric acid with 1%, water and salt water washing, and at MgSO 4Last dry.Concentrated solution also comes out its recrystallization from the EtOAc/ hexane, obtain (2,3-two chloro-phenyl)-ethanamide (4.50g, 22mmol).HPLC?Rt：5.52min。 1H-NMR(CDCl 3)：δ8.35(br.s，1H)，7.7(1H)，7.24(1H)，7.23(1H)，2.28(s，3H)。
Step 2:(2,3-two chloro-phenyl)-thioacetamide
Use P under the room temperature 2S 5(9.80g 22mmol) handles (2,3-two chloro-phenyl)-ethanamide (4.50g, 22mmol) solution in toluene (50mL).Reaction mixture is heated to 90 ℃ keeps 1.5h, be cooled to room temperature and filtration.Solid washs with ether, and washing lotion and filtrate are merged.The solution that NaOH aqueous solution extraction with 10% merges 2 times.0 ℃ of aqueous extract that merges with the HCl acidifying down.The collecting precipitation thing and from vinyl acetic monomer/hexane recrystallization come out, obtain (2,3-two chloro-phenyl)-thioacetamide (3.40g, 16mmol).HPLC?Rt：5.91min。 1H-NMR(CDCl 3)：δ8.80(br.s，1H，NH)，8.5(d，1H)，7.42(d，1H)，7.30(t，1H)，2.82(s，3H)。
Step 3:7-chloro-2-methyl-benzothiazole
(60% oil suspensions, 0.74g 19mmol) handle (2,3-two chloro-phenyl)-thioacetamide (3.4g, 15mmol) solution in N-N-methyl-2-2-pyrrolidone N-(25mL) with NaH under the room temperature.Reaction mixture is heated to 150 ℃ to be kept 30 minutes.Handle (EtOAc), dry (salt solution, MgSO 4), the evaporation and use the flash chromatography purifying, obtain title compound (2.4g, 13mmol).HPLC?Rt：6.65min。 1H-NMR(CDCl 3)：δ7.87(d，1H，J＝7.9Hz，ph-H)，7.44(t，1H，J＝7.9Hz，ph-H)，7.35(d，1H，J＝8.0Hz，ph-H)，2.87(s，3H，CH 3)。
Step 4:2-brooethyl-7-chloro-benzothiazole
Under the UV light irradiation, with 7-chloro-2-methyl-benzothiazole (1.00g, 5.45mmol), N-bromo-succinimide (1.26g, 7.08mmol), benzoyl peroxide (0.1g)) and CCl 4Mixture heating up (10mL) refluxes and keeps 14h.Reaction mixture also removes by filter the succimide that forms in the reaction, and filtrate is evaporated to drying.The solid of gained through the flash chromatography purifying obtain title compound (400mg, 1.5mmol). 1H-NMR(CDCl 3)：δ7.94(d，1H)，7.47(t，1H)，7.42(d，1H)，4.82(s，2H，CH2)。HPLC?Rt：7.19min。
Step 5:6-chloro-9-(7-chloro-benzothiazole-2-ylmethyl)-9H-purine-2-base amine
With 2-brooethyl-7-chloro-benzothiazole (60mg, 0.2286mmol), 2-amino-6-chloropurine (32mg, 0.19mmol), Cs 2CO 3(67.86mg, 0.208mmol) and the mixture heating up to 40 of DMF (2mL) ℃ keep 1h.Reaction is cooled to room temperature and on rotatory evaporator, removes and desolvate.Solid by preparation property TLC purifying gained obtain title compound (50mg, 0.14mmol).HPLC?Rt：5.81min。 1H-NMR(CDCl 3)：δ8.0(s，1H)，7.95(d，1H)，7.48(t，1H)，7.43(d，1H)，5.69(s，2H)，5.17(s，2H)。
Embodiment 181:6-chloro-9-(3,4,5-trimethylammonium-pyridine-2-ylmethyl)-9H-purine-2-base amine
Step 1:2,3,5-collidine-N-oxide compound
Referring to embodiment 1, method 1, step 1.
Step 2:4-bromo-2,3,5-collidine-N-oxide compound
Referring to embodiment 1, method 1, step 2.
Step 3:2,3,4,5 tetramethyl-s-pyridine 1-oxide compound
Under nitrogen, ((2g 9.2mmol) closes palladium (80mg, 4% weight) with catalytic four (triphenylphosphinyls) to 5-trimethylammonium-pyridine 1-oxide compound for the 2M solution in the toluene, 15.2mmol) the 4-bromo-2,3 among the processing 20mL exsiccant THF with trimethyl aluminium.Vlil is kept 3h,, use 4mL methyl alcohol and ammonium chloride subsequently (15mmol) cancellation reaction afterwards with toluene (20mL) dilution.Backflow mixture 2h also filters on diatomite while hot.Referring to J.Med.Chem.1999,42 (12), 2064-2086.HPLC?Rt：4.183min。 1H-NMR(CDCl 3)：δ8.05(s，1H)，2.55(s，3H)，2.27(s，3H)，2.22(s，3H)，2.20(s，3H)。
Step 4: acetic acid 3,4,5-trimethylammonium-pyridine-2-base methyl esters
As the description in the general step 2.2, reaction is dissolved in the acetic anhydride, the 0.5h that refluxes afterwards obtains compound.The water cancellation is reacted and is obtained title product with chloroform extraction.HPLC?Rt：3.843min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，5.22(s，2H)，2.26(s，3H)，2.25(s，3H)，2.21(s，3H)，2.11(s，3H)。
Step 5:(3,4,5-trimethylammonium-pyridine-2-yl)-methyl alcohol
As the description in the general step 2.3, under 50 ℃ with MeOH and K 2CO 3In acetic acid 3,4,5-trimethylammonium-pyridine-2-base methyl esters hydrolysis 0.5h obtains compound.After removing MeOH, be dissolved in residuum in the water and use chloroform extraction.HPLC?Rt：3.405min。 1H-NMR(CDCl 3)：δ8.18(s，1H)，5.00(s，1H)，4.67(s，2H)，2.28(s，3H)，2.23(s，3H)，2.12(s，3H)。
Step 6:2-brooethyl-3,4,5-trimethylammonium-pyridine
As the description in the general step 2.5, by in methylene dichloride, making (3,4,5-trimethylammonium-pyridine-2-yl)-methyl alcohol and triphenylphosphine and carbon tetrabromide prepared in reaction compound.HPLC?Rt：3.979min。 1H-NMR(CDCl 3)：δ8.18(s，1H)，4.63(s，2H)，2.35(s，3H)，2.48(s，3H)，2.24(s，3H)。
Step 7:6-chloro-9-(3,4,5-trimethylammonium-pyridine-2-ylmethyl)-9H-purine-2-base amine
As the description in the general step 1.1, under 50 ℃ at K 2CO 3Make 2-brooethyl-3,4 under existing, 5-trimethylammonium-pyridine and 6-chloro-9H-purine-2-base amine reaction 0.5h obtains compound.HPLC?Rt：3.903min。 1H-NMR(CDCl 3)：δ8.18(s，1H)，7.84(s，1H)，5.38(s，2H)，5.08(s，2H)，2.29(s，3H)，2.27(s，3H)，2.22(s，3H)。
Embodiment 182:6-bromo-9-(3,4,5-trimethylammonium-pyridine-2-ylmethyl)-9H-purine-2-base amine
As the description in the general step 1.1, under 50 ℃ at K 2CO 3Exist to make 2-brooethyl-3,4 down in DMF, 5-trimethylammonium-pyridine (referring to embodiment 117) obtains compound with 6-bromo-9H-purine-2-base amine reaction 0.5h.HPLC?Rt6：4.045min。 1H-NMR(CDCl 3)：δ8.18(s，1H)，7.85(s，1H)，5.37(s，2H)，5.10(s，2H)，2.29(s，3H)，2.27(s，3H)，2.22(s，3H)。
Embodiment 183:6-bromo-9-(3,4,5-trimethylammonium-1-oxygen-pyridine-2-ylmethyl)-9H-purine-2-base amine
As the description in the general step 2.1, in methylene dichloride, obtain compound with m-CPBA oxidation 6-chloro-9-(3,4,5-trimethylammonium-pyridine-2-ylmethyl)-9H-purine-2-base amine.HPLCRt：5.611min。 1H-NMR(CDCl 3)：δ9.13(s，1H)，8.08(s，1H)，5.91(s，2H)，2.70(s，3H)，2.27(s，3H)，2.22(s，3H)。
Biology embodiment
Adopt four tests to determine the biological activity of selected aminopurine: for biotinylation-geldanamycin (vitamin H-GM) measure with bonded restraining effect, lysate binding ability, HER2 degradation capability and the cytotoxicity of rHSP90.These the test before the part embodiment A, B, C and D in be described.Biological activity is summarized in the table 6.
The selected R of table 6. 3The biological activity of the formula II aminopurine of=H
Figure GSA00000083249103401
ND=does not determine
III. The preparation of pyrazolopyrimidine (formula III)
A. Material and method
Be used to generate the chemical reagent of following new product of the present invention all commercially available from, Aldrich Chemical Co. for example, Milwaukee, WI, the U.S..Otherwise then its preparation is easy to get and is known for those of ordinary skills very much, and perhaps it has mentioned in this article and describes.
Final compound adopts preparation property TLC (silica gel usually
Figure GSA00000083249103422
Whatman PartisilPK6F) or flash chromatography (silica gel The EMD chemical), use EtOAc/ hexane or MeOH/CH 2Cl 2Come purifying as eluent.Use silica gel tlc plate (silica gel
Figure GSA00000083249103431
The EMD chemical) measures the Rf value.Use C18 post (Agilent Zorbax 300SB-C18; 5 microns; 4.6mm * 150mm) obtain analytical HPLC chromatogram.Used constant flow rate 1mL/ minute, the ratio of A is increased to 100% (t=7.00 minute) by 5% (t=0) linearity, thereby at solvent orange 2 A (0.1%TFA in the water) and solvent B (CH 30.5%TFA among the CN) applies gradient between.Usually at MeOH or CH 3Among the CN sample is diluted to 0.1-1mg/mL, and volume injected is generally 10 μ L.Coupled columns does not heat, and carries out UV at the 254nm place and detects.Record on Bruker Avance 400MHz spectrograph 1H-NMR spectrum.
Use Beilstein Autonom 2.1 softwares to generate chemical name.
B. General step
1. The general step of preparation and conversion pyrazolo [3,4-d] pyrimidine ring
General step 1.1: the alkylation of pyrazolo [3,4-d] pyrimidine on the N-1 position
Figure GSA00000083249103432
According to Seela, F.; Stecker, H.Helv.Chim.Acta 1986,69, and the description among the 1602-1613 prepares 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine.Under 22-70 ℃ with 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine (1mmol), benzyl halide (mmol) and K 2CO 3(1-3mmol) suspension in exsiccant DMF (5mL) stirs 0.5-16h.Handle (EtOAc) and obtain the pure alkylating product in N-1 position through preparation property TLC or flash chromatography (EtOAc/ hexane) purifying.
Also [3,4-d] pyrimidine preparation of general step 1.2:3-alkyl pyrazole
Step 1:1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethanol
With 2-amino-4, and 6-two chloro-pyrimidine-5-formaldehydes (3.0g, 15mmol); (referring to Seela, F.; Stecker, H.Helv.Chim.Acta 1986,69,1602) delicate suspensions in THF is cooled to-78 ℃.Add the 3M solution of MeMgBr in THF (25mL, 75mmol, 5 equivalents) with 3h, keeping internal temperature is-78 ℃.With mixture restir 0.5h, use 100mL H 2The O cancellation is reacted, and neutralizes with aw.HCl.Obtain 1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethanol (2.5g, 76%) into light yellow solid through extraction (EtOAc), it uses without just being further purified.
Step 2:1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethyl ketone
Under 70 ℃,, use MnO in the 2-methylene dichloride in 1 2(20g, 229mmol, 24 equivalents) processing 1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethanol (2.0g, 9.6mmol).Filter on diatomite and concentrate, obtain being light orange solid 1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethyl ketone (1.4g, 6.7mmol, 71%), it uses without just being further purified.
Step 3:4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
(2-amino-4,6-two chloro-pyrimidine-5-yl)-(200mg 0.97mmol) is dissolved in CH to ethyl ketone with 1- 2Cl 2In and at room temperature use anhydrous hydrazine (31mg, 0.97mmol, 1 equivalent) to handle and spend the night.Filter the collecting precipitation thing, use CH 2Cl 2Washing is dissolved among the DMSO (0.5mL), and is distributed in EtOAc (100mL) and the water (25mL).Dry (salt solution, Na 2SO 4) and concentrate organic layer, obtain title compound (95mg, 0.52mmol, 53%) into white solid.
2. The general step of conversion pyridine ring
The preparation of general step 2.1:N-oxide compound
With pyridine derivate (1.0mmol) solution in ice bath cooling methylene dichloride or the chloroform (5mL), divide three parts of processing and make it be warming up to room temperature with m-CPBA (1.1-3mmol).Also use the NaOH aqueous solution and water washing subsequently with the dichloromethane extraction mixture.Dry (Na 2SO 4) and the concentrated pyridine N-oxides that obtains.
The preparation of general step 2.2:2-(acetoxy-methyl)-pyridine
The vlil of 2-PICOLINE N-OXIDES (1.0mmol) in acetic anhydride (5mL) kept 0.5h.Handle (EtOAc), dry (MgSO 4), evaporation and obtain 2-(acetoxy-methyl)-pyridine through preparation property TLC or flash chromatography purifying.
The preparation of general step 2.3:2-(hydroxymethyl)-pyridine
With 2-acetoxy-methyl-pyridine derivate and solid K 2CO 3Suspension in methyl alcohol is heated to 50 ℃ and kept 5-30 minute.Evaporation, processing (EtOAc) and dry (MgSO 4) obtain the 2-hydroxy-methyl pyridine.
The preparation of general step 2.4:2-(brooethyl)-pyridine
Solution in methylene dichloride or chloroform (5mL) is cooled to 0 ℃ with 2-(hydroxymethyl)-pyridine (1.0mmol) and triphenylphosphine (1.2mmol).CBr in drip dichloromethane or the chloroform 4(1.5mmol) solution, and under 0 ℃, stir gained mixture 0.5-1h.Handle afterwards and obtain 2-(brooethyl)-pyridine through the flash chromatography purifying.
The preparation of general step 2.5:2-chloropyridine
110 ℃ are stirred 2-(hydroxymethyl)-pyridine (10g) down at POCl 3Suspension 1.5h (30mL).The toughening oil of gained is cooled in room temperature and the impouring frozen water (500g).With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain 2-(chloromethyl)-pyridine, it typically is violet oil or solid, its not purified just use.
General step 2.6: the preparation of pyridinium salt
The heating pyridinium salt dissolves until it in MeOH.(solvent evaporated obtains pyridinium salt for 1.0 normal for example HCl, methanol solution MeOH) to add acid.
3. The general step of conversion phenyl ring
General step 3.1: the halogenation of phenyl ring
Variant 1: use Br under the room temperature 2(1.3 equivalent) handled the solution of aromatics in MeOH/THF/ acetic ester damping fluid (being 1N among each AcOH and the AcONa) 5 minutes.On rotatory evaporator, remove excessive bromine and solvent.Handle (CHCl 3) and through flash chromatography, the bromobenzene that obtains wishing.
Variant 2: aromatics (7mmol) in the acetic acid (40mL) and n-halogenated succinimide imide (NCS, NBS or NIS, 1.06 equivalents) solution are heated to 40-90 ℃ of maintenance 0.3-1h.Evaporation, the halogeno-benzene of handling (EtOAc) and obtaining wishing through flash chromatography.
C. The preparation of intermediate
Embodiment 184.2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
According to general step 3.1, with NCS chlorination 5-chloromethyl-1,2,3-trimethoxy-benzene obtains title compound. 1H-NMR(CDCl 3)：δ6.82(s，1H)，4.70(s，1H)，3.93(s，3H)，3.90(s，3H)3.87(s，3H)。
Embodiment 185.2-chloro-6-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine
Figure GSA00000083249103461
Step 1:2-chloromethyl-4-methoxyl group-3,5-lutidine-1-oxide compound
According to general step 2.1, by 2-chloromethyl-4-methoxyl group-3, the oxidation of 5-dimethyl-pyridine prepares title compound.R.t.：4.46min。 1H-NMR(CDCl 3)：δ8.05(s，1H)，4.93(s，2H)，3.77(s，3H)，2.37(s，3H)，2.24(s，3H)。
Step 2:2-chloro-6-chloromethyl-4-methoxyl group-3, the 5-lutidine
According to general step 2.5, use POCl 3Handle 2-chloromethyl-4-methoxyl group-3,5-lutidine-1-oxide compound obtains title compound.R.t.：6.757min。 1H-NMR(CDCl 3)：δ4.64(s，2H)，3.79(s，3H)，2.35(s，3H)，2.33(s，3H)。
Embodiment 186.4-chloro-2-chloromethyl-3,5-dimethyl-pyridine
In the mode identical, use POCl with general step 2.5 3Handle 2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol (Tarbit etc., WO 99/10326) obtains title compound (productive rate 74%).R.t.：5.54min。 1H-NMR(CDCl 3)：δ8.24(s，1H)，4.71(s，2H)，2.48(s，3H)，2.36(s，3H)。
Embodiment 187.4-bromo-2-brooethyl-3,5-dimethyl-pyridine
Prepare 4-bromo-2-brooethyl-3 with any method in following three kinds of methods, 5-dimethyl-pyridine:
Method 1
Step 1:2,3,5-collidine-N-oxide compound
According to general step 2.1, by oxidation 2,3, the 5-collidine obtains 2,3 with 70% productive rate, 5-collidine-N-oxide compound.R.t.：3.96min。 1H-NMR(CDCl 3)：δ8.03(s，1H)，6.90(s，1H)，2.47(s，3H)，2.31(s，3H)，2.24(s，3H)。m/z(％)138.2(M+1，100％)。Rf(20％MeOH/EtOAc)：0.35。
Step 2:4-bromo-2,3,5-collidine-N-oxide compound
With 2,3, and 5-collidine-N-oxide compound (1.3g, 10mmol) and K 2CO 3(2.9g 20mmol) is suspended in 10mL CCl 4In.(1mL is 20mmol) and with reaction mixture reflux 2h for dripping bromine.Handle (EtOAc) and obtain being solid title compound (1.05g, productive rate 51%) through flash chromatography (10%MeOH/EtOAc).R.t.：5.24min。 1H-NMR(CDCl 3)：δ8.06(s，1H)，2.56(s，3H)，2.43(s，3H)，2.31(s，3H)。m/z(％)216.2(M+1，100％)，218.2(M+3，100％)。Rf(20％MeOH/EtOAc)：0.45。
Step 3: acetic acid 4-bromo-3,5-dimethyl-pyridine-2-base methyl esters
With 4-bromo-2,3, (0.25g 11mmol) is dissolved in the acetic anhydride (5mL) and with vlil 30 minutes 5-collidine-N-oxide compound.Handle and process flash chromatography (50% hexane/EtOAc), obtain title compound (0.27g, productive rate 96%).Rf (50% hexane/EtOAc): 0.70.R.t.：4.76min。 1H-NMR(CDCl 3)：δ8.26(s，1H)，5.27(s，2H)，2.46(s，3H)，2.41(s，3H)，2.14(s，3H)。
Step 4:4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol
With acetic acid 4-bromo-3, and 5-dimethyl-pyridine-2-base methyl esters (0.26g, 1.0mmol) and K 2CO 3(excessive) suspension in MeOH (5mL) is heated to 50 ℃ and kept 15 minutes.Handle (CHCl 3), evaporation and filter (eluent: 100%EtOAc) obtain title compound (0.19g, productive rate 88%) into white solid by silicagel pad.Rf (50% hexane/EtOAc): 0.5.R.t.：3.80min。 1H-NMR(CDCl 3)：δ8.23(s，1H)，4.70(s，2H)，2.46(s，3H)，2.30(s，3H)。
Step 5:4-bromo-2-brooethyl-3,5-dimethyl-pyridine
According to general step 2.4, by 4-bromo-3,5-dimethyl-pyridine-2-base methyl alcohol obtains title compound.R.t.：6.32min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，4.63(s，2H)，2.52(s，3H)，2.40(s，3H)。
Method 2:
Step 1:2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol
According to the description among the patent WO 99/10326 of Tarbit etc., by heating 2-chloromethyl-4-methoxyl group-3 in toluene, 5-dimethyl-pyridine hydrochloride obtains title compound.
Step 2:4-bromo-2-chloromethyl-3,5-dimethyl-pyridine
Under 130 ℃ with 2-chloromethyl-3,5-dimethyl-pyridine-4-alcohol (8.2g, 47.8mmol) and POBr 3(60g, mixture 209mmol) stirs 3h.The toughening oil of gained is cooled in room temperature and the impouring frozen water.With solid KOH with pH regulator to 10.Handle (CHCl 3), dry (MgSO 4) and evaporation, obtain being purple solid title compound (8.7g, productive rate 78%) that it uses without just being further purified.R.t.：6.03min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，4.62(s，2H)，2.50(s，3H)，2.38(s，3H)。
Method 3:
4-bromo-2-chloromethyl-3, the 5-lutidine
With 2-chloromethyl-4-methoxyl group-3, (3.24g is 14.6mmol) at PBr for 5-dimethyl-pyridine under nitrogen 3Suspension in (8.0mL, 85.1mmol, 5.8 equivalents) is heated to 80 ℃.Add the DMF (0.50mL, 6.4mmol, 0.44 equivalent) of catalytic amount, suspension becomes orange solution rapidly therebetween.After 40 minutes, judge that through HPLC reaction is incomplete yet.Elevated temperature to 110 ℃ also will react and prolong 30 minutes, react completely at this moment.Use dense NH with the mixture impouring on ice, 4The OH aqueous solution is alkalescence and is extracted into EtOAc.Wash with water, dry (salt solution, MgSO 4) and concentrate, obtain title compound (1.51g, 44%), warp into pink solid 1H-NMR judges that it contains 10% impurity.Crude product uses without just being further purified. 1H-NMR(CDCl 3)：δ8.19(s，1H)，4.59(s，2H)，2.48(s，3H)，2.37(s，3H)。
D. The preparation of final compound
Embodiment 188.4-chloro-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 5-chloromethyl-1,2,3-trimethoxy-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtain title compound (referring to F.Seela, Heterocycles 1985,23,2521; F.Seela, Helv.Chim.Acta 1986,69, and 1602; R.O.Dempcy, the open No.WO 03/022859 of PCT).R.t.5.68min。 1H-NMR(CDCl 3)：δ7.93(s，1H)，6.59(s，2H)，5.37(br.s.，4H)，3.84(s，6H)，3.82(s，3H)。
Embodiment 189.4-chloro-1-(2-chloro-3,4,5-trimethoxy-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.44min。 1H-NMR(CDCl 3)：δ7.95(s，1H)，6.36(s，1H)，5.51(s，2H)，5.24(br.s，2H)，3.90(s，3H)，3.86(s，3H)，3.70(s，3H)。
Embodiment 190.4-chloro-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
With 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine (1.76g), 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine hydrochloride (3.70g), K 2CO 3(5.17g) and the mixture heating up to 80 of DMF (20mL) ℃ kept 30 minutes, with the EtOAc dilution, water and salt water washing, concentrate and, obtain title compound (0.57g) into white solid through the flash chromatography purifying.R.t.4.46min。 1H-NMR(CDCl 3)：δ8.10(s，1H)，7.89(s，1H)，5.53(2H)，5.24(br.s，2H)，3.74(s，3H)，2.27(s，3H)，2.22(s，3H)。
Embodiment 191.4-chloro-1-(6-chloro-4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
With 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine (124mg), Cs 2CO 3(392mg) and thick 2-chloro-6-chloromethyl-4-methoxyl group-3, the mixture heating up to 80 of 5-dimethyl-pyridine (200mg) in DMF (20mL) ℃ keeps 1h, with the EtOAc dilution and wash with water.Concentrate and obtain title compound through preparation property TLC (EtOAc) purifying.R.t.6.43min。 1H-NMR(CDCl 3)：δ7.86(s，1H)，5.48(s，2H)，5.37(s，2H)，3.71(s，3H)，2.27(s，3H)，2.15(s，3H)。
Embodiment 192.4-chloro-1-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
With 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine (158mg), thick 4-chloro-2-chloromethyl-3,5-dimethoxy-3,5-dimethyl-pyridine (204mg), Cs 2CO 3(660mg) and the mixture heating up to 80 of DMF ℃ keep 1.5h, with the EtOAc dilution and wash with water.Concentrated crude product also is suspended among the MeOH/DMC.Filtration obtains 2: 1 mixtures of regioisomer, and it is further purified through preparation property silica-gel plate (EtOAc 100%).Mainly the isomer of (polarity is less) is corresponding to title compound.R.t.5.45min。 1H-NMR(CDCl 3)：δ8.22(s，1H)，7.90(s，1H)，5.57(s，2H)，5.28(s，2H)，2.43(s，3H)，2.31(s，3H)。
Embodiment 193.4-chloro-1-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
With m-CPBA (90mg) to CH 2Cl 24-chloro-1-(2mL) (4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine (50mg) solution carries out 10 minutes processing, uses saturated NaHCO 3Solution washing concentrates and from CHCl 3Recrystallization comes out among/the MeOH, obtains the title compound into white solid.R.t.4.87min。 1H-NMR(DMSO-d6)：δ8.06(s，1H)，7.89(s，1H)，7.36(s，2H)，5.55(s，2H)，3.72(s，3H)，2.30(s，3H)，2.18(s，3H)。
Embodiment 194.4-chloro-1-(3,4-two chloro-benzyls)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 4-brooethyl-1,2-two chloro-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.89min。 1H-NMR(CDCl 3)：δ7.90(s，1H)，7.39-7.37(m，2H)，7.26(dd，1H)，5.37(s，2H)，5.20(br.s，2H)。
Embodiment 195.4-chloro-1-(2,5-dimethoxy-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 2-chloromethyl-1,4-dimethoxy-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.06min。 1H-NMR(CDCl 3)：δ7.94(s，1H)，6.85(d，1H)，6.75(dd，1H)，6.42(dd，1H)，5.48(s，2H)，5.24(s，2H)，3.82(s，3H)，3.70(s，3H)。
Embodiment 196.4-chloro-1-(4,5-dimethoxy-2-nitro-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 1-brooethyl-4,5-dimethoxy-2-nitro-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.99min。 1H-NMR(DMSO-d6)：δ8.06(s，1H)，7.71(s，1H)，7.38(br.s，2H)，6.57(s，1H)，5.71(s，2H)，3.86(s，3H)，3.68(s，3H)。
Embodiment 197.1-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.64min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，7.92(s，1H)，5.61(s，2H)，5.21(br.s，2H)，2.50(s，3H)，2.37(s，3H)。
Embodiment 198.1-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 2.1, obtain title compound with m-CPBA oxidation 1-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine.R.t.5.57min。 1H-NMR(CDCl 3)：δ8.23(s，1H)，7.90(s，1H)，7.38(s，2H)，5.64(s，2H)，2.50(s，3H)，2.30(s，3H)。
Embodiment 199.4-chloro-1-(2,3,6-three fluoro-benzyls)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 2-brooethyl-1,3,4-three fluoro-benzene, alkylation 4-chloro-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.7.12min。 1H-NMR(CDCl 3)：δ7.89(s，1H)，7.25-7.05(m，1H)，6.95-6.85(m，1H)，5.53(s，2H)，5.49(br.s，2H)。
Embodiment 200.1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethanol
According to general step 1.2, handle 2-amino-4-chloro-pyrimidine-5-formaldehyde with MeMgBr and obtain title compound.R.t.4.19min。 1H-NMR(DMSO-d 6)：δ7.38(s，1H)，5.18(bs，2H)，5.15(m，1H)，3.56(d，3H)。
Embodiment 201.1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethyl ketone
Figure GSA00000083249103521
According to general step 1.2, use MnO 2Handle 1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethanol, obtain title compound.R.t.5.23min。 1H-NMR(DMSO-d 6)：δ7.90(s，2H)，2.52(s，3H)。
Embodiment 202.4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103522
According to general step 1.2, handle 1-(2-amino-4,6-two chloro-pyrimidine-5-yl)-ethyl ketone with hydrazine, obtain title compound.R.t.4.61min。 1H-NMR(DMSO-d 6)：δ11.82(s，1H)，8.16(bs，2H)，2.46(s，3H)。
Embodiment 203.4-chloro-3-ethyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.2, use EtMgCl, MnO successively 2Handle 2-amino-4 with hydrazine, 6-two chloro-pyrimidine-5-formaldehydes obtain title compound.R.t.4.55min。 1H-NMR(DMSO-d 6)：δ12.84(s，1H)，7.07(s，2H)，2.85(m，2H)，1.27-1.23(m，3H)。
Embodiment 204.4-chloro-3-sec.-propyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103523
According to general step 1.2, use i-PrMgCl, MnO successively 2Handle 2-amino-4 with hydrazine, 6-two chloro-pyrimidine-5-formaldehydes obtain title compound.R.t.6.10min。 1H-NMR?(DMSO-d 6)：δ12.86(s，1H)，7.06(s，2H)，1.29(d，6H)。
Embodiment 205.4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103531
According to general step 1.2, use PhMgCl, MnO successively 2Handle 2-amino-4 with hydrazine, 6-two chloro-pyrimidine-5-formaldehydes obtain title compound.R.t.6.04min。 1H-NMR(DMSO-d 6)：δ13.04(s，1H)，7.70(m，2H)，7.46(m，3H)，7.19(bs，2H)。
Embodiment 206.4-chloro-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-3-methyl 1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.72min。 1H-NMR(CDCl 3)：δ8.20(s，1H)，5.47(s，2H)，5.26(s，2H)，3.76(s，2H)，2.58(s，3H)，2.30(s，3H)，2.23(s，3H)。
Embodiment 207.1-(4-bromo-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103533
According to general step 1.1, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.?5.90min。 1H-NMR(DMSO-d 6)：δ8.25(s，1H)，7.29(s，2H)，5.53(s，2H)，2.45(s，3H)，2.36(s，3H)，2.28(s，3H)。
Embodiment 208.4-chloro-1-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103541
According to general step 1.1, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.90min。 1H-NMR(DMSO-d 6)：δ8.25(s，1H)，7.30(s，2H)，5.54(s，2H)，2.45(s，3H)，2.36(s，3H)，2.28(s，3H)。
Embodiment 209.4-chloro-1-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103542
According to general step 1.1, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-3-methyl 1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.63min。 1H-NMR(CDCl 3)：δ8.23(s，1H)，5.51(s，2H)，5.28(br.s?2H)，2.57(s，3H)，2.45(s，3H)，2.33(s，3H)。
Embodiment 210.4-chloro-3-methyl isophthalic acid-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 5-chloromethyl-1,2,3-trimethoxy-benzene, alkylation 4-chloro-3-methyl 1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.72min。 1H-NMR(DMSO-d 6)：δ7.30(s，2H)，6.57(s，2H)，5.22(s，2H)，3.71(s，6H)，3.62(s，3H)，2.47(s，3H)，2.29(s，3H)。
Embodiment 211.1-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103551
According to general step 1.1, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.90min。 1H-NMR(DMSO-d 6)：δ8.15(s，1H)，7.22(s，1H)，5.46(s，2H)，2.42(s，6H)，2.30(s，3H)。
Embodiment 212.4-chloro-3-ethyl-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103552
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-3-ethyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.02min。 1H-NMR(DMSO-d 6)：δ8.04(s，1H)，7.19(br.s，1H)，5.39(s，2H)，3.71(s，3H)，2.87-2.81(m，2H)，2.22(s，3H)，2.16(s，3H)，1.21(m，3H)。
Embodiment 213.4-chloro-1-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-3-ethyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103561
According to general step 1.1, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-3-ethyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.90min。 1H-NMR(DMSO-d 6)：δ8.18(s，1H)，7.21(s，1H)，5.47(s，2H)，2.87-2.81(m，2H)，2.39(s，3H)，2.27(s，3H)，1.21(m，3H)。
Embodiment 214.4-chloro-3-sec.-propyl-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103562
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-3-sec.-propyl-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.75min。 1H-NMR(DMSO-d 6)：δ8.02(s，1H)，7.17(br.s，1H)，5.40(s，2H)，3.71(s，3H)，2.23(s，3H)，2.16(s，3H)，1.26(d，6H)。
Embodiment 215.4-chloro-1-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103563
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.5.89min。 1H-NMR(DMSO-d 6)：δ8.06(s，1H)，7.68-7.66(m，2H)，7.47-7.45(m，3H)，7.32(br.s，2H)，5.52(s，2H)，3.72(s，3H)，2.27(s，3H)，2.16(s，3H)。
Embodiment 216.4-chloro-1-(4-chloro-3,5-dimethyl-pyridine-2-ylmethyl)-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103571
According to general step 1.1, with 2-chloromethyl-4-methoxyl group-3,5-dimethyl-pyridine, alkylation 4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.6.80min。 1H-NMR(DMSO-d 6)：δ8.20(s，1H)，7.67-7.65(m，2H)，7.47-7.45(m，3H)，7.34(br.s，2H)，5.61(s，2H)，2.43(s，3H)，2.27(s，3H)。
Embodiment 217.1-(4-bromo-3,5-dimethyl-pyridine-2-ylmethyl)-4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
Figure GSA00000083249103572
According to general step 1.1, with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine, alkylation 4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.7.410min。 1H-NMR(DMSO-d 6)：δ8.15(s，1H)，7.67(m，2H)，7.46(m，3H)，7.34(br.s，2H)，5.62(s，2H)，2.4(s，3H)，2.3(s，3H)。
Embodiment 218.4-chloro-1-(4-chloro-3,5-dimethyl-1-oxygen-pyridine-2-ylmethyl)-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine
According to general step 1.1, with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide compound, alkylation 4-chloro-3-phenyl-1H-pyrazolo [3,4-d] pyrimidine-6-base amine obtains title compound.R.t.7.50min。 1H-NMR(DMSO-d 6)：δ8.25(s，1H)，7.57(s，2H)，7.42(m，5H)，5.67(s，2H)，2.49(s，3H)，2.26(s，3H)。
Biology embodiment
Adopt four tests to determine the biological activity of selected pyrazolopyrimidine: for biotinylation-geldanamycin (vitamin H-GM) measure with bonded restraining effect, lysate binding ability, HER2 degradation capability and the cytotoxicity of rHSP90.These the test before the part embodiment A, B, C and D in be described.Biological activity is summarized in the table 7.
The biological activity of the selected pyrazolopyrimidine of table 7.
Figure GSA00000083249103581
Figure GSA00000083249103591
Figure GSA00000083249103601
Figure GSA00000083249103611
ND=does not determine
IV. The preparation of the triazolo pyrimidine of formula IV
A. Material and method
Be used to generate the chemical reagent of following new product of the present invention all commercially available from, Aldrich Chemical Co. for example, Milwaukee, WI, the U.S..Otherwise then its preparation is easy to get and is known for those of ordinary skills very much, and perhaps it has mentioned in this article and describes.
Final compound adopts preparation property TLC (silica gel usually
Figure GSA00000083249103612
Whatman PartisilPK6F) or flash chromatography (silica gel
Figure GSA00000083249103613
The EMD chemical), use EtOAc/ hexane or MeOH/CH 2Cl 2Come purifying as eluent.Use silica gel tlc plate (silica gel
Figure GSA00000083249103614
The EMD chemical) measures the Rf value.Use C18 post (Agilent Zorbax 300SB-C18; 5 microns; 4.6mm * 150mm) obtain analytical HPLC chromatogram.Used constant flow rate 1mL/ minute, the ratio of A is increased to 100% (t=7.00 minute) by 5% (t=0) linearity, thereby at solvent orange 2 A (0.1%TFA in the water) and solvent B (CH 30.5%TFA among the CN) applies gradient between.Usually at MeOH or CH 3Among the CN sample is diluted to 0.1-1mg/mL, and volume injected is generally 10 μ L.Coupled columns does not heat, and carries out UV at the 254nm place and detects.Record on Bruker Avance 400MHz spectrograph 1H-NMR spectrum.
Use Beilstein Autonom 2.1 softwares to generate chemical name.
B. General step
1. The general step of preparation and conversion pyrazolo [3,4-d] pyrimidine ring
General step 1: replace chlorine with amine
Reference: Helv.Chim Acta.1986,69,1602-1613; US patent 5,917,042.
Backflow benzyl amine derivatives or aminomethyl pyridine derivatives (5.88mmol, 2.1 equivalents), triethylamine in n-BuOH or ethanol (10mL) (1mL, 7.2mmol) and 4,6-two chloro-pyrimidines-2,5-diamines (0.5g, mixture 3-18 2.8mmol) hour.Mixture is cooled to room temperature and uses CH 2Cl 2Extraction.Organic layer washes and uses MgSO with water 4Drying obtains crude product.Pyridinyl derivatives chromatogram (100%EtOAc-10%MeOH/EtOAc) purifying, and benzyl derivative uses without just being further purified.
General step 2: cyclisation forms the triazolo pyrimidine ring system
Under 0 ℃, to 6-chloro-N 4-benzyl-pyrimidine-2,4,5-triamine derivative or 6-chloro-N 4-pyridine-2-ylmethyl-pyrimidine-2,4,5-triamine derivative (0.57mmol) is at 25%HOAc/H 2Drip NaNO in the solution among the O 2The aqueous solution (1.2 equivalents, 1mL).At room temperature stirred the mixture 15 minutes, and filtered crude product and through using the column chromatography purifying of 75%EtOAc/ hexane-100%EtOAc.
General step 3: aromatic ring halogenation
Under 50 ℃, with 7-chloro-3-benzyl-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl amine derivatives (0.57mmol) and NCS (N-chlorosuccinimide) or NBS (N-bromo-succinimide) or the mixture of NIS (N-iodo succimide) (1.5 equivalent) in 10mL HOAc stirred 1-15 hour, obtain corresponding halogenation crude product, it uses chromatogram (50-75%EtOAc/ hexane) purifying again.
The formation of general step 4:N-oxide compound
Cool off the solution of pyridine derivate (1mmol) in methylene dichloride or chloroform (5mL) with ice bath, divide three parts of processing and make it be warming up to room temperature with m-CPBA (1.1-3mmol).Mixture is with dichloromethane extraction and use the NaOH aqueous solution and water washing subsequently.Dry (Na 2SO 4) and the concentrated pyridine N-oxides that obtains.
Embodiment 219.7-chloro-3-(4-methoxyl group-3,5-lutidine-2-yl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine
Step 1:2-amino methyl-4-methoxyl group-3,5-lutidine synthetic:
With 2-chloromethyl-4-methoxyl group-3, (Aldrich 3.7g is 16.6mmol) at 7N NH for 5-dimethyl-pyridine HCl in steel bomb 3(Aldrich, 200mL) solution in refluxed 15 hours/MeOH.Removal of solvent under reduced pressure is absorbed into residuum 5% MeOH/CH 2Cl 2In and through the thin layer filtered through silica gel, the productive rate with 76% obtains product.HPLC RT is 2.850min. 1H-NMR(CDCl 3)：δ8.18(s，1H)，4.32(s，2H)，3.76(s，3H)，2.23(s，3H)，2.18(s，3H)。
Step 2:6-chloro-N 4-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-pyrimidine-2,4,5-triamine synthetic
According to general step 1, in n-BuOH with 4,6-two chloro-pyrimidines-2,5-diamines and 2-amino-ethyl-4-methoxyl group-3, the mixture heating up backflow 3h of 5-dimethyl-pyridine.HPLC RT is 3.597min. 1H-NMR(CDCl 3)：δ8.22(s，1H)，7.12(br.t，1H)，4.61(s，2H)，4.56-4.55(d，2H)，3.80(s，3H)，3.00(s，2H)，2.29(s，3H)，2.27(s，3H)。
Step 3:7-chloro-3-(4-methoxyl group-3,5-lutidine-2-yl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-pyrimidine-2,4, the solution of 5-triamine.HPLC RT is 3.597min. 1H-NMR(CDCl 3)：δ8.22(s，1H)，7.12(br.t，1H)，4.61(s，2H)，4.56-4.55(d，2H)，3.80(s，3H)，3.00(s，2H)，2.29(s，3H)，2.27(s，3H)。
Embodiment 220.7-chloro-3-(4-methoxyl group-3,5-dimethyl-1-oxygen-pyridine-2-yl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine
According to general step 4, with m-CPBA (m-chloroperoxybenzoic acid) oxidation 7-chloro-3-(4-methoxyl group-3,5-dimethyl-pyridine-2-the ylmethyl)-3H-[1 in the methylene dichloride, 2,3] triazolo [4,5-d] pyrimidine-5-base amine (referring to embodiment 1) obtains compound.HPLC RT is 4.780min. 1H-NMR(CDCl 3)：δ8.02(s，1H)，5.90(s，2H)，5.61(s，2H)，3.81(s，3H)，2.54(s，3H)，2.25(s，3H)。
Embodiment 221.7-chloro-3-(4-methoxyl group-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine
Step 1:6-chloro-N 4-(4-methoxyl group-benzyl)-pyrimidine-2,4,5-triamine synthetic:
According to general step 1, in n-BuOH, reflux 4,6-two chloro-pyrimidines-2, the mixture 15h of 5-diamines and 1-amino methyl-4-anisole.HPLC RT is 4.675min. 1H-NMR(CDCl 3)：δ7.29-7.27(d，2H)，6.91-6.89(d，2H)，5.62(br.t，1H)4.67(s，2H)，4.56-4.54(d，2H)，3.84(s，3H)，2.74(s，2H)。
Step 2:7-chloro-3-(4-methoxyl group-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-(4-methoxyl group-phenyl)-pyrimidine-2,4, the solution of 5-triamine.HPLC RT is 5.784min. 1H-NMR(CDCl 3)：δ7.37-7.35(d，2H)，6.86-6.84(d，2H)，5.57(s，2H)，5.39(s，2H)，3.78(s，3H)。
Embodiment 222.7-chloro-3-pyridine-2-ylmethyl-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
Step 1:6-chloro-N 4-pyridin-2-yl-methyl-pyrimidine-2,4, the 5-triamine
According to general step 1, in n-BuOH, reflux 4,6-two chloro-pyrimidines-2, the mixture 15h of 5-diamines and 2-aminomethyl pyridine.HPLC RT is 2.573min. 1H-NMR(CDCl 3)：δ8.60-8.59(m，1H)，7.69-7.66(m，1H)，7.31-7.29(m，1H)，7.25-7.20(m，1H)，6.55(br.t，1H)4.63(s，2H)，4.73-4.71(d，2H)，1.84(s，2H)。
Step 2:7-chloro-3-pyridine-2-ylmethyl-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic:
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-pyridine-2-ylmethyl-pyrimidine-2,4, the solution of 5-triamine. 1H-NMR(CDCl 3)：δ8.60-8.59(m，1H)，7.71-7.67(m，1H)，7.29-7.25(m，1H)，7.22-7.20(m，1H)，5.81(s，2H)，5.48(s，2H)。
Embodiment 223.7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
Step 1:6-chloro-N 4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4, the 5-triamine
According to general step 1, in n-BuOH, reflux 4,6-two chloro-pyrimidines-2,5-diamines and 1-amino methyl 3,4, the mixture 15h of 5-trimethoxy-benzene.HPLC RT is 4.458min. 1H-NMR(CDCl 3)：δ6.58(s，2H)，5.62(br.t，1H)4.72(s，2H)，4.56-4.54(d，2H)，3.88(s，6H)，3.86(s，3H)，2.77(s，2H)。
Step 2:7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic:
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4, the solution of 5-triamine.HPLC RT is 5.755min. 1H-NMR(CDCl 3)：δ6.66(s，2H)，5.55(s，2H)，5.42(s，2H)，3.83(s，3H)，3.80(s，6H)。
Embodiment 224.7-chloro-3-(2-chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According to general step 3, with NCS (1.5 equivalent) chlorination 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2137), obtain 7-chloro-3-(2-chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine: HPLCRT is 6.244min. 1H-NMR(CDCl 3)：δ6.53(s，1H)，5.70(s，2H)，5.48(s，2H)，3.89(s，3H)，3.87(s，3H)，3.75(s，3H)。
Embodiment 225.7-chloro-3-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine
According to general step 3, with NCS (1.5 equivalent) chlorination 7-chloro-3-(3,4,5-trimethoxy-benzyl)-and 3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2137), obtain 7-chloro-3-(2,6-two chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine: HPLC RT is 6.616min. 1H-NMR(CDCl 3)：δ5.81(s，2H)，5.47(s，2H)，3.97(s，3H)，3.90(s，6H)。
Embodiment 226.7-chloro-3-(2-bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According to general step 3, with NBS (1.5 equivalent) bromination 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2137), obtain 7-chloro-3-(2-bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine: HPLCRT is 6.541min. 1H-NMR(CDCl 3)：δ6.52(s，1H)，5.74(s，2H)，5.46(s，2H)，3.93(s，3H)，3.89(s，3H)，3.76(s，3H)。
Embodiment 227.7-chloro-3-(2,6-two bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2564)
According to general step 3, with NBS (1.5 equivalent) bromination 7-chloro-3-(3,4,5-trimethoxy-benzyl)-and 3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2137), obtain 7-chloro-3-(2,6-two bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine: HPLC RT is 6.923min. 1H-NMR(CDCl 3)：δ5.91(s，2H)，5.51(s，2H)，3.99(s，3H)，3.93(s，6H)。
Embodiment 228.7-chloro-3-(2-iodo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According to general step 3, with NIS (1.5 equivalent) iodate 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine (CF 2137), obtain title compound.HPLC RT is 6.497min. 1H-NMR(CDCl 3)：δ6.47(s，1H)，5.73(s，2H)，5.44(s，2H)，3.92(s，3H)，3.88(s，3H)，3.73(s，3H)。
Embodiment 229.7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
Step 1:6-chloro-N 4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4, the 5-triamine
According to general step 1, in n-BuOH, reflux 4,6-two chloro-pyrimidines-2,5-diamines and 1-amino methyl 3, the mixture 15h of 5-dimethoxy benzene.HPLC RT is 4.835min. 1H-NMR(CDCl 3)：δ6.46-6.47(d，2H)，6.38-6.37(d，1H)，5.67(br.t，1H)4.63(s，2H)，4.53-4.52(d，2H)，3.81(s，6H)，2.72(s，2H)。
Step 2:7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic:
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4, the solution of 5-triamine.HPLC RT is 6.185min. 1H-NMR(CDCl 3)：δ6.54-6.53(d，2H)，6.41-6.40(d，1H)，5.58(s，2H)，5.54(s，2H)，3.78(s，6H)。
Embodiment 230.7-chloro-3-(2-chloro-3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According under 3,50 ℃ of the general steps in acetic acid with NCS (1.5 equivalent) to 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine carries out the chlorination of 1h, obtains title compound.HPLC RT is 6.467min. 1H-NMR(CDCl 3)：δ6.50-6.49(d，1H)，6.18-6.17(d，1H)，5.77(s，2H)，5.44(s，2H)，3.91(s，3H)，3.72(s，3H)。
Embodiment 231.7-chloro-3-(2-bromo-3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According under 3,50 ℃ of the general steps in acetic acid with NBS (1.5 equivalent) to 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine carries out the bromination of 1h, obtains title compound.HPLC RT is 6.573min. 1H-NMR(d 6-DMSO)：δ7.74(s，2H)，6.70-6.69(d，1H)，6.23-6.22(d，1H)，5.63(s，2H)，3.87(s，3H)，3.71(s，3H)。
Embodiment 232.7-chloro-3-(2-iodo-3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According under 3,50 ℃ of the general steps in acetic acid with NIS (1.5 equivalent) to 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine carries out the iodate of 1h, obtains title compound.HPLC RT is 6.739min. 1H-NMR(d 6-DMSO)：δ7.75(s，2H)，6.61-6.60(d，1H)，6.15-6.14(d，1H)，5.58(s，2H)，3.86(s，3H)，3.70(s，3H)。
Embodiment 233.7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
Step 1:6-chloro-N 4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4, the 5-triamine
According to general step 1, in n-BuOH, reflux 4,6-two chloro-pyrimidines-2,5-diamines and 1-amino methyl 2, the mixture 15h of 5-dimethoxy benzene.HPLC RT is 4.601min. 1H-NMR(CDCl 3)：δ6.91-6.90(d，1H)，6.82-6.80(m，2H)，5.82(br.t，1H)4.62(s，2H)，4.59-4.58(d，2H)，3.85(s，3H)，2.78(s，3H)，2.75(s，2H)
Step 2:7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic:
According to general step 2, with cold NaNO 2The aqueous solution is handled 6-chloro-N 4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4, the solution of 5-triamine.HPLC RT is 6.130min. 1H-NMR(CDCl 3)：δ6.84-6.83(m，2H)，6.64-6.63(d，1H)，5.67(s，2H)，5.54(s，2H)，3.83(s，3H)，3.73(s，3H)。
Embodiment 234.7-chloro-3-(4-bromo-2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According under 3,50 ℃ of the general steps in acetic acid with NBS (1.5 equivalent) to 7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine carries out the bromination of 1h, obtains title compound.HPLC RT is 6.438min. 1H-NMR(CDCl 3)：δ7.11(s，1H)，6.80(s，1H)，5.63(s，2H)，5.57(s，2H)，3.82(s，3H)，3.79(s，3H)。
Embodiment 235.7-chloro-3-(3-chloro-2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine is synthetic
According under 3,50 ℃ of the general steps in acetic acid with NCS (1.5 equivalent) to 7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amine carries out the chlorination of 1h, obtains title compound.HPLC RT is 6.392min. 1H-NMR(CDCl 3)：δ6.91-6.90(d，1H)，6.67-6.66(d，1H)，5.70(s，2H)，5.43(s，2H)，3.92(s，3H)，3.73(s，3H)。
Biology embodiment
Adopt four tests to determine the biological activity of selected triazolo pyrimidine: for biotinylation-geldanamycin (vitamin H-GM) measure with bonded restraining effect, lysate binding ability, HER2 degradation capability and the cytotoxicity of rHSP90.These the test before the part embodiment A, B, C and D in be described.Biological activity is summarized in the table 8.
The biological activity of the selected formula IV triazolo pyrimidine of table 8.
Figure GSA00000083249103691
Figure GSA00000083249103692
Figure GSA00000083249103701
Figure GSA00000083249103711
ND=does not determine
Previous embodiment is nonrestrictive, and it only illustrates different aspect of the present invention and embodiment.All documents of quoting have herein all showed the state of the art in the affiliated field of the present invention, and its full content is incorporated herein by reference.But any document is not thought prior art.
Those skilled in the art are readily appreciated that, can change well to realize its purpose and to reach above-mentioned target and profitable and some things of inherent wherein the present invention.The method and composition of describing has illustrated embodiment preferred, and it limits scope of the present invention for exemplary being not intended.Those skilled in the art can expect some modification and other purposes, and it is included in as in the defined spirit of the present invention of the scope of claim.
The present invention who describes with illustrative approach herein can suitably not have the form of concrete disclosed one or more elements, one or more qualifications to put into practice herein to lack arbitrarily.Term that uses and expression are used as descriptive term rather than restrictive, and use this term to be not intended to get rid of any shown and the feature of description or the equivalent form of value of its a plurality of parts with expressing.Should be realized that in the scope of the invention that requires, various modification to be arranged.Therefore, though it is concrete open to should be appreciated that the present invention has been undertaken by preferred embodiment, but the optional feature of definition disclosed herein, modification and variant can be adopted by those skilled in the art, and this modification and variant also are considered in as specification sheets and the defined scope of the present invention of claims.
In addition, for optional with Ma Kushi group or other, the feature of the present invention or the aspect that are described of the group of kind for example, those skilled in the art should be realized that, the present invention also describes with any separate member of Ma Kushi group or group or each member's group in view of the above, and, for example get rid of independent member by collateral condition with appropriate form.

Claims (18)

1. the compound of formula I representative, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000011
Wherein:
R 0Be selected from hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-CN and-NHR 8
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NHR 8
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical and heterocyclic radical, all groups are optional to be substituted, wherein:
Described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring;
R 8And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N, and
R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 0Or R 3For-OH or-SH, described compound can be used as the mixture of (sulphur) keto tautomer accordingly or keto-enol tautomerism body and exists;
R 4For-CHR 12-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
Described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2Or-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl or low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl or rudimentary heteroaryl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary heteroaryl or lower aryl; With
R 12Be hydrogen or low alkyl group.
2. the compound of claim 1, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 0For hydrogen, halogen ,-SH ,-OH or-CN;
R 1Be halogen;
R 2For-NH 2
R 3For hydrogen, halogen ,-OR 8,-SR 8,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, lower aryl or rudimentary heteroaryl, wherein R 8For hydrogen, low alkyl group, lower aryl or-(CO) R 9
R 4For-CH 2-; With
R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups.
3. the compound of claim 2, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein R 1Be chlorine or bromine, R 2For-NH 2, and R 5For having at least 3 substituent phenyl, having at least 2 substituent pyridyl; Or have at least 2 substituent 1-Oxopyridyls (N-Oxopyridyl).
4. be selected from down a compound in the group, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000031
Figure FSA00000083249000041
Figure FSA00000083249000051
Figure FSA00000083249000061
Figure FSA00000083249000081
Figure FSA00000083249000091
5. be selected from down a compound in the group, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000101
As shown in the formula one of structural formula representative compound, or its polymorphic form, solvate, ester, tautomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000111
Figure FSA00000083249000121
Figure FSA00000083249000131
Figure FSA00000083249000141
7. the compound of formula IC representative, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000142
Insert IC
Wherein:
R 0For hydrogen, halogen, low alkyl group ,-SR 8,-OR 8,-CN or-NHR 8
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NH 2
R 4For-CHR 12-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein:
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2Or-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein work as R 8And R 10Former together form slection becomes the ring of 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10The optional together ring that forms 3～7 annular atomses, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group; With
R 0And R 10The optional formation that link together chosen substituted exocyclic double bond wantonly, or optional ring and optional 1～3 annular atoms that forms 3～7 annular atomses is the heteroatoms that is selected from O, S and N.
8. the compound of claim 7, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 0Be hydrogen;
R 1Be halogen;
R 4For-CH 2-;
R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; With
R 10Be hydrogen.
9. the compound of claim 8, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein: R 1Be chlorine or bromine; R 5Be phenyl, pyridyl or 1-Oxopyridyl (N-Oxopyridyl), each R 5Have at least two substituting groups.
10. be selected from down a compound in the group, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000171
11. the compound of formula ID representative, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug:
Figure FSA00000083249000172
ID
Wherein:
R 1For halogen ,-OR 11,-SR 11Or low alkyl group;
R 2For-NH 2
R 3Be selected from hydrogen, halogen ,-SR 8,-OR 8,-CN ,-C (O) R 9,-C (O) OH ,-NO 2,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, aryl, heteroaryl, alicyclic radical and heterocyclic radical, all groups are optional to be substituted, wherein:
Described aryl, heteroaryl, alicyclic radical and heterocyclic radical optional for single-, two-or three-ring, R 8And R 10Optional ring and optional 1～3 annular atoms that forms 3～7 annular atomses that link together is the heteroatoms that is selected from O, S and N, and
R 3On optional substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 4For-CHR 12-;
R 5Be aryl, heteroaryl, alicyclic radical or heterocyclic radical, wherein
Described aryl is replaced by 3～5 substituting groups,
Described heteroaryl is replaced by 2～5 substituting groups,
Described alicyclic radical is replaced by 3～5 substituting groups,
Described heterocyclic radical is replaced by 3～5 substituting groups, and
R 5On described substituting group be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl ,-SR 8,-OR 8,-CN ,-C (O) OH ,-C (O) R 9,-NO 2,-NR 8R 10, lower aryl, heteroaryl, alicyclic radical, rudimentary heterocyclic radical, aralkyl, heteroaralkyl, amino, alkylamino, dialkyl amido, alkyl diaryl amino, oxo, oxa-, whole haloalkyl, perhalogeno alkoxyl group, perhalogeno acyl group, guanidine, pyridyl, thiophene, furyl, indoles, indazole, phosphonic acid ester, phosphoric acid ester, phosphamide, sulphonate, sulfone, sulfuric ester, sulphonamide, carbamate, urea, thiocarbamide and thioamides, wherein R 8And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 8For hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 9For H, low alkyl group, lower aryl, rudimentary heteroaryl ,-NR 10R 10Or-OR 11, R wherein 10And R 10Link together and choose the ring that forms 3～7 annular atomses wantonly, and optional 1～3 annular atoms is the heteroatoms that is selected from O, S and N;
R 10Be hydrogen, low alkyl group, rudimentary heteroaryl, lower aryl, low-grade alkenyl or low-grade alkynyl;
R 11Be low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary heteroaryl or lower aryl;
R 12Be hydrogen or low alkyl group; With
R 3And R 10The optional formation that link together chosen substituted exocyclic double bond wantonly, or optional ring and optional 1～3 annular atoms that forms 3～7 annular atomses is the heteroatoms that is selected from O, S and N.
12. the compound of claim 11, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein:
R 1Be halogen;
R 3For hydrogen, halogen ,-OR 8,-SR 8,-NR 8R 10, low alkyl group, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, lower aryl or rudimentary heteroaryl, wherein R 8For hydrogen, low alkyl group, low-grade alkenyl or low-grade alkynyl, lower aryl, rudimentary heteroaryl or-(CO) R 9
R 4For-CH 2-;
R 5Be aryl or heteroaryl, wherein each described aryl and heteroaryl are monocycle or dicyclo and are replaced by 3～5 substituting groups; With
R 10Be hydrogen or low alkyl group.
13. the compound of claim 12, or its polymorphic form, solvate, ester, tautomer, enantiomer, pharmacy acceptable salt or prodrug, wherein: R 1Be chlorine or bromine; And R 5Be phenyl, pyridyl or 1-Oxopyridyl (N-Oxopyridyl) that each group has at least two substituting groups.
14. a pharmaceutical composition comprises one or more pharmaceutically acceptable excipient and at least one according to each compound among the claim 1-13.
15. a method that suppresses HSP90 comprises: make cell and contact according to each compound among the claim 1-13 with HSP90.
16. the method that the individuality of the illness of suffering from HSP90 mediation is treated, comprise to described individual administration comprise medicine effective quantity, according to claim 1-13 in each the pharmaceutical composition of compound.
17. the method for claim 16, wherein the illness of HSP90 mediation is selected from inflammatory diseases, infection, autoimmune disorder, apoplexy, local asphyxia, cardiac conditions, nervous disorders, fibrosis illness, and wherein said fibrosis illness further is selected from scleroderma, polymyositis, system's lupus, rheumatoid arthritis, liver cirrhosis, cicatrization, interstitial nephritis and pulmonary fibrosis, proliferative disorders, tumour, leukemia, vegetation, cancer, cancer knurl, metabolic trouble and malignant disease.
18. the method for claim 17, it further comprises at least a therapeutical agent that is selected from cytotoxic agent, anti-angiogenic agent and antineoplastic agent of administration, and wherein said at least a antineoplastic agent is selected from alkylating agent, anti--metabolite, epipodophyllotoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum complex, biological respinse modifier and growth inhibitor, hormone/anti--hormonotherapy agent and hemopoieticgrowth factor.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857763A (en) * 2017-11-28 2018-03-30 江苏杏睿生物科技有限公司 A kind of adjacent nitro aroylation derivatives quasi-compound, preparation method and applications
CN111918653A (en) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 Novel MTOR inhibitor compounds
CN115925724A (en) * 2022-11-16 2023-04-07 成都中医药大学 A kind of adenine compound with anti-inflammatory effect and its preparation method and application
CN116332940A (en) * 2023-02-14 2023-06-27 广西民族大学 A kind of 7-deazapurine derivative and its preparation method and application

Families Citing this family (186)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6992188B1 (en) * 1995-12-08 2006-01-31 Pfizer, Inc. Substituted heterocyclic derivatives
KR100850727B1 (en) * 2000-11-02 2008-08-06 슬로안-케테링인스티튜트퍼캔서리서치 Small molecule compositions for binding to hsp90
EP1463742A4 (en) * 2001-06-21 2006-05-10 Ariad Pharma Inc Novel pyrazolo-and pyrrolo-pyrimidines and uses thereof
EP1440072A4 (en) * 2001-10-30 2005-02-02 Conforma Therapeutic Corp Purine analogs having hsp90-inhibiting activity
US20070129334A1 (en) * 2001-10-30 2007-06-07 Conforma Therapeutics Corporation Orally Active Purine-Based Inhibitors of Heat Shock Protein 90
BRPI0414533A (en) 2003-09-18 2006-11-07 Conforma Therapeutics Corp compound, pharmaceutical composition, and methods for inhibiting an hsp90 and treating an individual having an hsp90 mediated disorder
US8741578B2 (en) * 2004-11-02 2014-06-03 The Regents Of The University Of California Methods of detecting chronic lymphocytic leukemia with Hsp90 and ZAP-70
AU2005302000A1 (en) * 2004-11-02 2006-05-11 Conforma Therapeutics Corporation Methods and compositions for treating chronic lymphocytic leukemia
US9120774B2 (en) 2004-11-03 2015-09-01 University Of Kansas Novobiocin analogues having modified sugar moieties
US8212012B2 (en) * 2004-11-03 2012-07-03 University Of Kansas Novobiocin analogues having modified sugar moieties
WO2006105372A2 (en) * 2005-03-30 2006-10-05 Conforma Therapeutics Corporation Alkynyl pyrrolopyrimidines and related analogs as hsp90-inhibitors
WO2006109075A2 (en) * 2005-04-13 2006-10-19 Astex Therapeutics Limited Hydroxybenzamide derivatives and their use as inhibitors of hsp90
AU2006236557A1 (en) * 2005-04-14 2006-10-26 Novartis Vaccines And Diagnostics Inc. 2-amino-quinazolin-5-ones as HSP90 inhibitors useful in treating proliferation diseases
WO2006124897A2 (en) * 2005-05-13 2006-11-23 Lexicon Genetics Incorporated Methods and compositions for improving cognition
CA2615946A1 (en) * 2005-07-22 2007-02-01 Sunesis Pharmaceuticals, Inc. Pyrazolo pyrimidines useful as aurora kinase inhibitors
AU2006283592A1 (en) 2005-08-22 2007-03-01 Amgen Inc. Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators
ES2577514T3 (en) 2005-08-22 2016-07-15 The Regents Of The University Of California TLR antagonists
EP1919482A1 (en) * 2005-08-24 2008-05-14 Lexicon Pharmaceuticals, Inc. Pyrrolopyridine, pyrrolopyrimidine and pyrazolopyridine compounds, compositions comprising them, and methods of their use
WO2007035963A2 (en) * 2005-09-23 2007-03-29 Conforma Therapeutics Corporation Anti-tumor methods using multi drug resistance independent synthetic hsp90 inhibitors
JP2009515884A (en) * 2005-11-10 2009-04-16 スミスクライン・ビーチャム・コーポレイション Inhibitor of AKT activity
JP2009517342A (en) * 2005-11-10 2009-04-30 スミスクライン・ビーチャム・コーポレイション Inhibitor of AKT activity
EP1962863A4 (en) * 2005-12-22 2010-11-24 Conforma Therapeutics Corp Orally active purine-based inhibitors of heat shock protein 90
WO2007092496A2 (en) * 2006-02-07 2007-08-16 Conforma Therapeutics Corporation 7,9-dihydro-purin-8-one and related analogs as hsp90-inhibitors
US8658633B2 (en) * 2006-02-16 2014-02-25 Massachusetts Eye And Ear Infirmary Methods and compositions for treating conditions of the eye
NZ572600A (en) * 2006-05-12 2011-08-26 Myrexis Inc 6-Amino-purine derivatives for the treatment of cancer and fibrogenetic disorders
US8846697B2 (en) * 2006-05-31 2014-09-30 The Regents Of The University Of California Purine analogs
US10336757B2 (en) 2006-06-30 2019-07-02 Sloan-Kettering Institute For Cancer Research Treatment of neurodegenerative diseases through inhibition of HSP90
US20080009508A1 (en) * 2006-07-10 2008-01-10 Lucie Szucova 6,9-Disubstituted Purine Derivatives And Their Use For Treating Skin
ATE414281T1 (en) * 2006-08-03 2008-11-15 Cellzome Ag METHOD FOR IDENTIFYING MOLECULES THAT INTERACT WITH PI3K AND METHOD FOR PURIFYING PI3K
KR20140127367A (en) 2006-09-19 2014-11-03 다이이찌 산쿄 가부시키가이샤 Pyrazolopyrimidine derivative
WO2008045529A1 (en) * 2006-10-12 2008-04-17 Serenex, Inc. Purine and pyrimidine derivatives for treatment of cancer and inflammatory diseases
CL2007002994A1 (en) * 2006-10-19 2008-02-08 Wyeth Corp HETEROCICLIC DERIVATIVE COMPOUNDS CONTAINING SULFAMOIL, INHIBITORS OF HSP90; PHARMACEUTICAL COMPOSITION; AND USE FOR THE TREATMENT OF CANCER, SUCH AS CANCER OF BREAST, COLON AND PROSTATE, BETWEEN OTHERS.
FR2907453B1 (en) * 2006-10-24 2008-12-26 Sanofi Aventis Sa NOVEL FLUORENE DERIVATIVES, COMPOSITIONS CONTAINING SAME AND USE THEREOF
GB0622084D0 (en) * 2006-11-06 2006-12-13 Chroma Therapeutics Ltd Inhibitors of HSP90
EP2108019A2 (en) * 2007-01-30 2009-10-14 Biogen Idec MA, Inc. 1-h-pyrazolo[3,4b]pyrimidine derivatives and their use as modulators of mitotic kinases
DE602008003404D1 (en) * 2007-02-01 2010-12-23 Astrazeneca Ab 5,6,7,8-TETRAHYDROPTERIDINE DERIVATIVES AS HSP90 INHIBITORS
PT2510946E (en) 2007-02-07 2015-11-23 Univ California Conjugates of synthetic tlr agonists and uses therefor
KR101313804B1 (en) * 2007-03-20 2013-10-01 쿠리스 인코퍼레이션 Fused amino pyridine as hsp90 inhibitors
CA2684169C (en) 2007-04-12 2012-06-19 Joyant Pharmaceuticals, Inc. Smac mimetic dimers and trimers useful as anti-cancer agents
US8143265B2 (en) * 2007-04-16 2012-03-27 Meharry Medical College Method of treating atherosclerosis
US7960353B2 (en) * 2007-05-10 2011-06-14 University Of Kansas Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders
DE102007028521A1 (en) * 2007-06-21 2008-12-24 Merck Patent Gmbh Indazolamidderivate
EP2200653A2 (en) 2007-09-10 2010-06-30 University of Massachusetts Mitochondria-targeted anti-tumour agents
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
GB2467670B (en) 2007-10-04 2012-08-01 Intellikine Inc Chemical entities and therapeutic uses thereof
WO2009086170A1 (en) 2007-12-21 2009-07-09 Joyant Pharmaceuticals, Inc. Diazonamide analogs with improved solubility
US8895701B2 (en) 2008-01-05 2014-11-25 Sloan-Kettering Institute For Cancer Research Peptide-conjugated oligonucleotide therapeutic and method of making and using same
CN102088974A (en) * 2008-02-07 2011-06-08 加利福尼亚大学校务委员会 Treatment of bladder disease with TLR7 activators
US8190543B2 (en) * 2008-03-08 2012-05-29 Tokyo Electron Limited Autonomous biologically based learning tool
WO2009114470A2 (en) * 2008-03-10 2009-09-17 Curis, Inc. Tetrahydroindole and tetrahdyroindazole as hsp90 inhibitors containing a zinc binding moiety
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
WO2009114870A2 (en) 2008-03-14 2009-09-17 Intellikine, Inc. Kinase inhibitors and methods of use
JP5123429B2 (en) 2008-04-29 2013-01-23 ジョイアント ファーマスーティカルズ、インク． Indoline anticancer agent
LT5623B (en) 2008-04-30 2010-01-25 Biotechnologijos Institutas, , 5-aryl-4-(5-substituted 2,4-dihydroxyfenil)-1,2,3-thiadiazoles as inhibitors of hsp90 chaperone and the intermediates for production thereof
EP2273882A4 (en) * 2008-05-13 2011-07-13 Poniard Pharmaceuticals Inc BIOACTIVE COMPOUNDS FOR THE TREATMENT OF CANCER AND NEURODEGENERATIVE DISEASES
WO2009143485A1 (en) 2008-05-22 2009-11-26 Joyant Pharmaceuticals, Inc. Diazonamide analogs
WO2010006086A2 (en) 2008-07-08 2010-01-14 Intellikine, Inc. Kinase inhibitors and methods of use
WO2010014617A1 (en) * 2008-07-28 2010-02-04 University Of Kansas Heat shock protein 90 inhibitor dosing methods
GB0819102D0 (en) * 2008-10-17 2008-11-26 Chroma Therapeutics Ltd Pyrrolo-pyrimidine compounds
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
WO2010065275A1 (en) * 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
CA2786715C (en) * 2009-01-16 2019-05-21 Curis, Inc. Fused amino pyridines for the treatment of brain tumors
WO2010088924A1 (en) 2009-02-06 2010-08-12 Telormedix Sa Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration
EA019768B1 (en) * 2009-02-11 2014-06-30 Дзе Регентс Оф Дзе Юниверсити Оф Калифорния Compounds modulating activity of toll-like receptors
WO2010098344A1 (en) * 2009-02-25 2010-09-02 第一三共株式会社 Tricyclic pyrazolopyrimidine derivative
EP3578664B1 (en) * 2009-03-30 2024-10-30 Nordic Bioscience A/S Collagen iv neo-epitope fibrosis assay
TW201102391A (en) * 2009-03-31 2011-01-16 Biogen Idec Inc Certain substituted pyrimidines, pharmaceutical compositions thereof, and methods for their use
CA2766100C (en) 2009-06-29 2018-05-22 Incyte Corporation Pyrimidinones as pi3k inhibitors
AU2010269674B2 (en) * 2009-07-10 2014-01-16 Taiho Pharmaceutical Co., Ltd. Azabicyclo compound and salt thereof
PE20121148A1 (en) 2009-08-17 2012-09-07 Intellikine Llc HETEROCYCLIC COMPOUNDS AND USES OF THEM
WO2011041593A1 (en) * 2009-09-30 2011-04-07 University Of Kansas Novobiocin analogues and treatment of polycystic kidney disease
LT2486039T (en) 2009-10-07 2016-10-10 Sloan Kettering Institute For Cancer Research Purine derivatives useful as hsp90 inhibitors
EP2493879B1 (en) 2009-10-28 2014-05-14 Joyant Pharmaceuticals, Inc. Dimeric smac mimetics
US20110130711A1 (en) * 2009-11-19 2011-06-02 Follica, Inc. Hair growth treatment
WO2011075643A1 (en) 2009-12-18 2011-06-23 Incyte Corporation Substituted heteroaryl fused derivatives as pi3k inhibitors
WO2011075630A1 (en) * 2009-12-18 2011-06-23 Incyte Corporation Substituted fused aryl and heteroaryl derivatives as pi3k inhibitors
AR079545A1 (en) 2009-12-21 2012-02-01 Bayer Cropscience Ag TIENILPIRI (MI) DINILAZOL
WO2011130342A1 (en) 2010-04-14 2011-10-20 Incyte Corporation FUSED DERIVATIVES AS ΡI3Κδ INHIBITORS
CA2797315C (en) 2010-04-30 2018-09-11 Telormedix Sa Phospholipid drug analogs
US9050319B2 (en) 2010-04-30 2015-06-09 Telormedix, Sa Phospholipid drug analogs
EP2571361A4 (en) 2010-05-19 2013-11-13 Univ North Carolina PYRAZOLOPYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
WO2011163195A1 (en) 2010-06-21 2011-12-29 Incyte Corporation Fused pyrrole derivatives as pi3k inhibitors
KR20130099006A (en) 2010-08-23 2013-09-05 다이이찌 산쿄 가부시키가이샤 Free crystal of tricyclic pyrazolopyrimidine derivative
JP5701884B2 (en) 2010-08-23 2015-04-15 第一三共株式会社 Crystals of tricyclic pyrazolopyrimidine derivatives
EP2638014B1 (en) 2010-11-08 2017-01-04 Lycera Corporation N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of ror-gamma activity and the treatment of diseases
KR20140099556A (en) 2010-12-16 2014-08-12 에프. 호프만-라 로슈 아게 Tricyclic pi3k inhibitor compounds and methods of use
WO2012083181A1 (en) * 2010-12-16 2012-06-21 Indiana University Research And Technology Corporation Alpha helix mimetics and methods for using
ES2764848T3 (en) 2010-12-20 2020-06-04 Incyte Holdings Corp N- (1- (substituted phenyl) ethyl) -9H-purine-6-amines as PI3K inhibitors
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US8362023B2 (en) 2011-01-19 2013-01-29 Hoffmann-La Roche Inc. Pyrazolo pyrimidines
CA2825028A1 (en) * 2011-02-09 2012-08-16 F. Hoffman-La Roche Ag Heterocyclic compounds as pi3 kinase inhibitors
TWI592411B (en) 2011-02-23 2017-07-21 英特爾立秦有限責任公司 Combination of kinase inhibitors and uses thereof
WO2012125629A1 (en) 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
KR101984480B1 (en) 2011-04-05 2019-05-31 슬로안-케테링인스티튜트퍼캔서리서치 Hsp90 inhibitors
MX360390B (en) 2011-04-05 2018-10-31 Sloan Kettering Inst Cancer Res Hsp90 inhibitors.
LT2699580T (en) 2011-04-22 2018-01-10 Joyant Pharmaceuticals, Inc. Diazonamide analogs
EP2714688B1 (en) 2011-05-26 2016-02-24 Daiichi Sankyo Company, Limited Heterocyclic compounds as protein kinase inhibitors
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
ITTO20110652A1 (en) * 2011-07-20 2013-01-21 Medestea Res & Production S P A COMPOUND DERIVED FROM THE ADENINE HAVING IMMUNO-MODULATING ACTION, ANTI-INFLAMMATORY AND ANTI-DOLUTION ACTION
KR102131612B1 (en) 2011-09-02 2020-07-08 인사이트 홀딩스 코포레이션 Heterocyclylamines as pi3k inhibitors
MX2014004086A (en) 2011-10-03 2014-09-22 Univ North Carolina Pyrrolopyrimidine compounds for the treatment of cancer.
AR090548A1 (en) 2012-04-02 2014-11-19 Incyte Corp BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS
RU2014149136A (en) 2012-05-08 2016-07-10 Мерк Шарп И Доум Корп. TETRAHYDRONAFTHYRIDINE AND RELATED Bicyclic Compounds for Inhibition of Rorγ Activity and Treatment of a Disease
JP6242868B2 (en) 2012-05-08 2017-12-06 リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ Tetrahydro [1,8] naphthyridinesulfonamide and related compounds for use as agonists of RORγ and for the treatment of diseases
JP2015516464A (en) * 2012-05-15 2015-06-11 カルアジア ファーマシューティカルズ，インコーポレイテッド Pyrimidinediamine derivatives as inhibitors of cytoplasmic Hsp90
WO2013177168A1 (en) 2012-05-22 2013-11-28 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
CN107652289B (en) 2012-06-13 2020-07-21 因塞特控股公司 Substituted tricyclic compounds as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
EP2904119B1 (en) 2012-10-02 2020-06-17 The General Hospital Corporation d/b/a Massachusetts General Hospital Methods relating to dna-sensing pathway related conditions
JP2015531395A (en) 2012-10-04 2015-11-02 ファイザー・リミテッドＰｆｉｚｅｒ Ｌｉｍｉｔｅｄ Pyrrolo [3,2-C] pyridine tropomyosin-related kinase inhibitor
CN103724269B (en) * 2012-10-11 2016-12-21 中国科学院上海药物研究所 Phenyl 1, 2-isoxazole or phenyl 1, 2-pyrazole compound and application thereof
US9562047B2 (en) 2012-10-17 2017-02-07 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
WO2014085225A1 (en) 2012-11-27 2014-06-05 The University Of North Carolina At Chapel Hill Pyrimidine compounds for the treatment of cancer
HRP20180859T1 (en) 2012-12-07 2018-07-13 Vertex Pharmaceuticals Incorporated 2-Amino-6-fluoro-N- (5-fluoro-4- (4- (4- (3-oxetanyl-yl) piperazine-1-carbonyl) piperidin-1-yl) pyridin-3-yl) pyrazolo [ 1,5ALFA] PIRIMIDINE-3-CARBOXAMIDE AS ATR KINASE INHIBITOR
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
WO2014144715A1 (en) 2013-03-15 2014-09-18 Memorial Sloan-Kettering Cancer Center Hsp90-targeted cardiac imaging and therapy
EP2970286A1 (en) 2013-03-15 2016-01-20 Vertex Pharmaceuticals Inc. Fused pyrazolopyrimidine derivatives useful as inhibitors of atr kinase
JP2016512239A (en) 2013-03-15 2016-04-25 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ Compounds useful as inhibitors of ATR kinase
EP2970288A1 (en) 2013-03-15 2016-01-20 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2014145576A2 (en) * 2013-03-15 2014-09-18 Northwestern University Substituted pyrrolo(2,3-d)pyrimidines for the treatment of cancer
US9724354B2 (en) 2013-03-22 2017-08-08 Millennium Pharmaceuticals, Inc. Combination of catalytic mTORC1/2 inhibitors and selective inhibitors of Aurora A kinase
KR102269032B1 (en) 2013-04-19 2021-06-24 인사이트 홀딩스 코포레이션 Bicyclic heterocycles as fgfr inhibitors
AU2014293011A1 (en) 2013-07-26 2016-03-17 Race Oncology Ltd. Compositions to improve the therapeutic benefit of bisantrene
CN105899503B (en) 2013-08-16 2020-08-18 纪念斯隆-凯特琳癌症中心 Selective GRP94 inhibitors and uses thereof
HRP20192183T1 (en) 2013-12-06 2020-02-21 Vertex Pharmaceuticals Inc. COMPOUND 2-AMINO-6-FLUORO-N- [5-FLUORO-PYRIDIN-3-YL] PYRAZOLO [1,5-A] PYRIMIDINE-3-CARBOXAMIDE USEFUL AS AN ATR KINASE INHIBITOR, ITS PREPARATION, VARIOUS DIFFERENT MARKED DERIVATIVES
WO2015095795A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE, AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE
WO2015095792A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Carbamate benzoxaxine propionic acids and acid derivatives for modulation of rorgamma activity and the treatment of disease
WO2015095788A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. 2-ACYLAMIDOMETHYL AND SULFONYLAMIDOMETHYL BENZOXAZINE CARBAMATES FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE
US10532088B2 (en) 2014-02-27 2020-01-14 Lycera Corporation Adoptive cellular therapy using an agonist of retinoic acid receptor-related orphan receptor gamma and related therapeutic methods
ES2548927B1 (en) * 2014-03-21 2016-08-11 Universidad De Granada Purine derivatives as Dapk-1 inhibitors
WO2015157127A1 (en) 2014-04-11 2015-10-15 The University Of North Carolina At Chapel Hill Therapuetic uses of selected pyrimidine compounds with anti-mer tyrosine kinase activity
US9896441B2 (en) 2014-05-05 2018-02-20 Lycera Corporation Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
US10189777B2 (en) 2014-05-05 2019-01-29 Lycera Corporation Benzenesulfonamido and related compounds for use as agonists of RORγ and the treatment of disease
EP3152212B9 (en) 2014-06-05 2020-05-27 Vertex Pharmaceuticals Inc. Radiolabelled derivatives of a 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]- pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof
WO2015191677A1 (en) 2014-06-11 2015-12-17 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as pi3k inhibitors
EP3157566B1 (en) 2014-06-17 2019-05-01 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of chk1 and atr inhibitors
KR20170052687A (en) 2014-09-17 2017-05-12 메모리얼 슬로안-케터링 캔서 센터 Hsp90-targeted inflammation and infection imaging and therapy
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
KR101713638B1 (en) * 2014-11-18 2017-03-08 한국과학기술연구원 Novel pyrrolo pyrimidine derivatives and composition for preventing or treating cancer comprising the same
CA2975997A1 (en) 2015-02-11 2016-08-18 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as rorgammat inhibitors and uses thereof
PE20171514A1 (en) 2015-02-20 2017-10-20 Incyte Corp BICYCLE HETEROCYCLES AS FGFR INHIBITORS
WO2016134294A1 (en) 2015-02-20 2016-08-25 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
MA41551A (en) 2015-02-20 2017-12-26 Incyte Corp BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS
SI3831833T1 (en) 2015-02-27 2023-03-31 Incyte Holdings Corporation Processes for the preparation of a pi3k inhibitor
US10421751B2 (en) 2015-05-05 2019-09-24 Lycera Corporation Dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
WO2016183060A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
WO2016183063A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Crystalline forms of a pi3k inhibitor
WO2016201225A1 (en) 2015-06-11 2016-12-15 Lycera Corporation Aryl dihydro-2h-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of rory and the treatment of disease
CN107922396B (en) * 2015-07-20 2022-08-05 建新公司 Colony stimulating factor-1 receptor (CSF-1R) inhibitors
HK1258570A1 (en) 2015-09-30 2019-11-15 Vertex Pharmaceuticals Inc. Method for treating cancer using a combination of dna damaging agents and atr inhibitors
US10287272B2 (en) 2015-10-27 2019-05-14 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
EP3368535B1 (en) 2015-10-27 2020-12-02 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as rorgammat inhibitors and uses thereof
WO2017075178A1 (en) 2015-10-27 2017-05-04 Merck Sharp & Dohme Corp. SUBSTITUTED BICYCLIC PYRAZOLE COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
US10709708B2 (en) 2016-03-17 2020-07-14 The University Of North Carolina At Chapel Hill Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor
US11697851B2 (en) 2016-05-24 2023-07-11 The Regents Of The University Of California Early ovarian cancer detection diagnostic test based on mRNA isoforms
KR101896616B1 (en) * 2016-10-11 2018-09-07 한국과학기술연구원 2-Amino-purine derivative compound, preparing method and use thereof
KR102053933B1 (en) * 2016-10-26 2019-12-11 울산과학기술원 Compound as TRAP1 inhibitor and pharmaceutical composition for anticancer comprising the same
SMT201900517T1 (en) 2017-03-20 2019-11-13 Forma Therapeutics Inc Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators
AR111960A1 (en) 2017-05-26 2019-09-04 Incyte Corp CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION
US10472361B2 (en) * 2017-08-16 2019-11-12 Bristol-Myers Squibb Company Toll-like receptor 7 (TLR7) agonists having a benzotriazole moiety, conjugates thereof, and methods and uses therefor
JOP20180094A1 (en) 2017-10-18 2019-04-18 Hk Inno N Corp Heterocyclic compound as a protein kinase inhibito
FR3075795A1 (en) 2017-12-21 2019-06-28 Galderma Research & Development NEW MTOR INHIBITOR COMPOUNDS
EP3762385B1 (en) 2018-03-09 2025-02-12 Recurium IP Holdings, LLC Substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones
SG11202010636VA (en) 2018-05-04 2020-11-27 Incyte Corp Solid forms of an fgfr inhibitor and processes for preparing the same
BR112020022373A2 (en) 2018-05-04 2021-02-02 Incyte Corporation salts of a fgfr inhibitor
IL278889B2 (en) 2018-06-01 2025-11-01 Incyte Corp Dosage regimen for the treatment of PI3K-related disorders
US12324807B2 (en) 2018-06-01 2025-06-10 Cornell University Combination therapy for PI3K-associated disease or disorder
US20200129485A1 (en) 2018-09-19 2020-04-30 Forma Therapeutics, Inc. Treating sickle cell disease with a pyruvate kinase r activating compound
CN113226356B (en) 2018-09-19 2025-03-04 诺沃挪第克健康护理股份公司 Pyruvate kinase R
KR102195348B1 (en) 2018-11-15 2020-12-24 에이치케이이노엔 주식회사 Novel compound as a protein kinase inhibitor, and the pharmaceutical composition comprising thereof
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
CN114615977B (en) 2019-09-19 2025-01-14 诺沃挪第克健康护理股份公司 Pyruvate Kinase R (PKR) activating compositions
WO2021067374A1 (en) 2019-10-01 2021-04-08 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021076602A1 (en) 2019-10-14 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
JP7720840B2 (en) 2019-12-04 2025-08-08 インサイト・コーポレイション Tricyclic heterocycles as FGFR inhibitors
CN115151539A (en) 2019-12-04 2022-10-04 因赛特公司 Derivatives of FGFR Inhibitors
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
KR102516260B1 (en) * 2020-07-10 2023-03-31 울산과학기술원 Compounds as a TRAP1 selective inhibitor, and composition for preventing or treating cancer comprising the same
EP4267573A1 (en) 2020-12-23 2023-11-01 Genzyme Corporation Deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors
US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
AR126102A1 (en) 2021-06-09 2023-09-13 Incyte Corp TRICYCLIC HETEROCYCLES AS FGFR INHIBITORS
CA3220155A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors

Family Cites Families (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB884151A (en) 1957-12-06 1961-12-06 Ciba Ltd New pyrazolo-pyrimidines substituted in the pyrazole nucleus, and process for their manufacture
IL64501A (en) 1980-12-22 1985-07-31 Astra Laekemedel Ab 9-substituted 4-hydroxybutyl guanine derivatives,their preparation and antiviral use
US4699877A (en) 1982-11-04 1987-10-13 The Regents Of The University Of California Methods and compositions for detecting human tumors
US4806642A (en) 1984-10-05 1989-02-21 Warner-Lambert Company Purine derivatives
US5098906A (en) 1983-10-31 1992-03-24 Warner-Lambert Company Purine derivatives
US4921859A (en) 1983-10-31 1990-05-01 Warner-Lambert Company Purine derivatives
US4547573A (en) 1983-12-02 1985-10-15 Ici Pharma Process for preparing cephalosporin derivatives
DE3578499D1 (en) * 1984-02-02 1990-08-09 Merck & Co Inc 5- (AMINO OR SUBSTITUTED AMINO) -1,2,3-TRIAZOLE.
US4748177A (en) 1984-03-26 1988-05-31 Warner-Lambert Company Guanine derivatives
US4617304A (en) * 1984-04-10 1986-10-14 Merck & Co., Inc. Purine derivatives
IT1196261B (en) 1984-09-20 1988-11-16 Pierrel Spa 8-SUBSTITUTED NUCLEOSIDIC AND PURINIC DERIVATIVES
ZA857647B (en) * 1984-10-12 1986-05-28 Warner Lambert Co Purine derivatives
IL76546A (en) 1984-10-12 1988-12-30 Warner Lambert Co 9-(heteroarylalkyl)-6-purine(thi)one derivatives,their preparation and pharmaceutical compositions containing them
US4772606A (en) 1985-08-22 1988-09-20 Warner-Lambert Company Purine derivatives
JO1406B1 (en) 1984-11-02 1986-11-30 سميث كلاين اند فرينش لابوراتوريز ليمتد Chemical compounds
DE3687030T2 (en) 1985-03-15 1993-03-11 Eugene Stirchak STEREO-REGULAR POLYNUCLEOTID-BINDING POLYMERS.
US5217866A (en) 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
IL78643A0 (en) 1985-05-02 1986-08-31 Wellcome Found Purine derivatives,their preparation and pharmaceutical compositions containing them
GB8515934D0 (en) 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
US4918162A (en) * 1986-05-06 1990-04-17 The Regents Of The University Of California Assays and antibodies for N-MYC proteins
DE3623099C3 (en) * 1986-07-09 1998-08-13 Spoetzl Markus Dipl Ing Fh Blow molding machine
US5002950A (en) 1986-10-24 1991-03-26 Warner-Lambert Co. 7-deazaguanines as immunomodulators
US4968603A (en) 1986-12-31 1990-11-06 The Regents Of The University Of California Determination of status in neoplastic disease
US5204353A (en) 1987-04-07 1993-04-20 Ciba-Geigy Corporation 3-benzyl-3H-1,2,3-triazolo[4,5-d]pyrimidines, compositions thereof, and method of treating epilepsy therewith
JPH0821101B2 (en) 1987-07-21 1996-03-04 三洋電機株式会社 Coin sorter
SE8801729D0 (en) 1988-05-06 1988-05-06 Astra Ab PURINE DERIVATIVES FOR USE IN THERAPY
US4923885A (en) * 1988-08-19 1990-05-08 Merck & Co., Inc. 5-amino-1-(4-naphthoylbenzyl)-1,2,3-triazole-4-carboxamides and analogs as antiproliferative agents
EP0363320A3 (en) 1988-10-06 1991-11-21 Ciba-Geigy Ag Substituted 9h purine
US5332744A (en) 1989-05-30 1994-07-26 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0465297B1 (en) 1990-07-04 1996-01-31 Merrell Dow Pharmaceuticals Inc. 9-Purinyl phosphonic acid derivatives
GB9020931D0 (en) 1990-09-26 1990-11-07 Wellcome Found Heterocyclic compounds
ATE187173T1 (en) 1991-03-05 1999-12-15 Ajinomoto Kk CYCLOPROPANE DERIVATIVE
US5939420A (en) 1991-04-08 1999-08-17 Duquesne University Of The Holy Ghost Pyrrolo 2,3d!derivatives
WO1992021032A1 (en) * 1991-05-24 1992-11-26 The Regents Of The University Of California Methods for the detection of bcr-abl and abnormal abl proteins in leukemia patients
US6025126A (en) * 1991-10-28 2000-02-15 Arch Development Corporation Methods and compositions for the detection of chromosomal aberrations
CA2093403C (en) 1992-04-08 1999-08-10 Fumio Suzuki Therapeutic agent for parkinson's disease
JPH0680670A (en) 1992-09-03 1994-03-22 Ajinomoto Co Inc Cyclopropane derivative and its production
GB9226879D0 (en) * 1992-12-23 1993-02-17 Iaf Biochem Int Anti-viral compounds
US6444656B1 (en) * 1992-12-23 2002-09-03 Biochem Pharma, Inc. Antiviral phosphonate nucleotides
US6005107A (en) * 1992-12-23 1999-12-21 Biochem Pharma, Inc. Antiviral compounds
US5744492A (en) 1993-09-17 1998-04-28 United States Of America Method for inhibiting angiogenesis
US5602156A (en) 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
GB9402161D0 (en) * 1994-02-04 1994-03-30 Wellcome Found Chloropyrimidine intermediates
JP3769737B2 (en) 1994-03-30 2006-04-26 味の素株式会社 Cyclopropane derivative and process for producing the same
US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US6110923A (en) 1994-06-22 2000-08-29 Biochem Pharma Inc. Method for treating cancer using novel substituted purinyl derivatives with immunomodulating activity
US5525606A (en) 1994-08-01 1996-06-11 The United States Of America As Represented By The Department Of Health And Human Services Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines
JPH0841035A (en) 1994-08-05 1996-02-13 Ajinomoto Co Inc Cyclopropane derivative and its production
US5846749A (en) 1994-10-12 1998-12-08 The Regents Of The University Of California Quantitative measurement of tissue protein identified by immunohistochemistry and standardized protein determination
JPH08208687A (en) 1994-11-25 1996-08-13 Sankyo Co Ltd Glyceryl oligonucleotide
US5656629A (en) * 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
US6177460B1 (en) * 1995-04-12 2001-01-23 The Procter & Gamble Company Method of treatment for cancer or viral infections
JPH0920776A (en) 1995-06-30 1997-01-21 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antiviral agent with the same as active ingredient
JPH09169758A (en) 1995-10-18 1997-06-30 Nippon Paper Ind Co Ltd New purine nucleoside derivative, its production and antivirus using the same
JPH1025294A (en) 1996-03-26 1998-01-27 Akira Matsuda Fused heterocyclic derivative, method for producing the same, and therapeutic agent for malignant tumor containing the same
CA2230808C (en) 1996-07-03 2006-08-15 Japan Energy Corporation A novel purine derivative
US6723727B1 (en) 1996-12-20 2004-04-20 Hoechst Aktiengesellschaft Substituted purine derivatives, processes for their preparation, their use, and compositions comprising them
US6284748B1 (en) 1997-03-07 2001-09-04 Metabasis Therapeutics, Inc. Purine inhibitors of fructose 1,6-bisphosphatase
US5861503A (en) * 1997-04-30 1999-01-19 The Regents Of The University Of California Process for producing 8-fluoropurines
CA2287387C (en) 1997-05-14 2010-02-16 Sloan-Kettering Institute For Cancer Research Methods and compositions for destruction of selected proteins
IL133800A0 (en) 1997-07-03 2001-04-30 Du Pont Pharm Co Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
ES2253821T3 (en) 1997-07-12 2006-06-01 Cancer Research Technology Limited PURINE DERIVATIVES QUINASE INHIBITORS THAT DEPENDS ON CYCLINE.
GB9717849D0 (en) 1997-08-23 1997-10-29 Seal Sands Chemicals Limited Preparation of pyridene derivatives
AUPO912997A0 (en) 1997-09-11 1997-10-02 Commonwealth Scientific And Industrial Research Organisation Antiviral agents
US5968921A (en) * 1997-10-24 1999-10-19 Orgegon Health Sciences University Compositions and methods for promoting nerve regeneration
CA2309350C (en) 1997-11-12 2007-04-03 Mitsubishi Chemical Corporation Purine derivatives and medicaments comprising the same as active ingredient
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
AU3378599A (en) 1998-04-03 1999-10-25 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
US5985060A (en) 1998-07-25 1999-11-16 Breed Automotive Technology, Inc. Gas generant compositions containing guanidines
SI20022A (en) 1998-07-29 2000-02-29 Kemijski inštitut Alkyl substituted purine derivatives and their preparation
JP2000072773A (en) 1998-08-28 2000-03-07 Zeria Pharmaceut Co Ltd Purine derivatives
US6369092B1 (en) * 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
WO2000040597A1 (en) * 1999-01-06 2000-07-13 University Of Southern California Method and composition for angiogenesis inhibition
CZ27399A3 (en) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituted nitrogen heterocyclic derivatives process of their preparation, the derivatives employed as medicaments, pharmaceutical composition and a compound pharmaceutical preparation in which these derivatives are comprised as well as use of these derivatives for preparing medicaments
RU2001124352A (en) 1999-02-01 2004-02-20 Си Ви Терапьютикс, Инк. (Us) Purine inhibitors of cyclin-dependent kinase 2 and Ikb-alpha
FR2790702B1 (en) 1999-03-08 2001-07-20 Sidel Sa MOLDING UNIT AND EXTRUSION-BLOWING MACHINE PROVIDED WITH SUCH A UNIT
US6174875B1 (en) * 1999-04-01 2001-01-16 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
AU4589800A (en) 1999-05-05 2000-11-21 Darwin Discovery Limited 9-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,9-dihydropurin-6-one derivatives as pde7inhibitors
US6660845B1 (en) * 1999-11-23 2003-12-09 Epoch Biosciences, Inc. Non-aggregating, non-quenching oligomers comprising nucleotide analogues; methods of synthesis and use thereof
CO5271715A1 (en) 1999-12-21 2003-04-30 Sugen Inc 7-AZA-INDOLIN-2-WAVES SUBSTITUTED IN 4 AND ITS USE AS PROTEIUNA QUINASA INHIBITORS
US20030187261A1 (en) 2000-01-07 2003-10-02 Libor Havlicek Purine derivatives, process for their preparation and use thereof
EP1265913A4 (en) 2000-03-24 2004-07-14 Univ Duke CHARACTERIZATION OF LIGANDS-GRP94 INTERACTIONS AND RELATED PURIFICATION, SCREENING AND PROCESSING METHODS
US6667300B2 (en) * 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
NZ522076A (en) 2000-04-25 2005-08-26 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
WO2002002123A1 (en) 2000-06-29 2002-01-10 Trustees Of Boston University Use of geldanamycin and related compounds for prophylaxis or treatment of fibrogenic disorders
WO2002009696A1 (en) 2000-07-28 2002-02-07 Sloan-Kettering Institute For Cancer Research Methods for treating cell proliferative disorders and viral infections
US6613089B1 (en) 2000-10-25 2003-09-02 Sdgi Holdings, Inc. Laterally expanding intervertebral fusion device
EP1337275A4 (en) 2000-11-02 2007-05-09 Sloan Kettering Inst Cancer METHOD FOR IMPROVING THE EFFICACY OF CYTOTOXIC AGENTS BY USING HSP90 INHIBITORS
KR100850727B1 (en) 2000-11-02 2008-08-06 슬로안-케테링인스티튜트퍼캔서리서치 Small molecule compositions for binding to hsp90
GB0100623D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds IV
GB0100624D0 (en) * 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds VII
GB0100621D0 (en) * 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds VI
MY141789A (en) * 2001-01-19 2010-06-30 Lg Chem Investment Ltd Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same.
CA2440809A1 (en) 2001-03-01 2002-09-12 Conforma Therapeutics Corp. Methods for treating genetically-defined proliferative disorders with hsp90 inhibitors
US6881567B2 (en) * 2001-03-16 2005-04-19 Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Agricultural And Agri-Food Canada Pre-emergent biological control agents
CA2444130C (en) 2001-04-17 2010-12-21 Sumitomo Pharmaceuticals Company, Limited Adenine derivatives
US20020156277A1 (en) * 2001-04-20 2002-10-24 Fick David B. Synthesis and methods of use of purine analogues and derivatives
US20030022864A1 (en) * 2001-04-24 2003-01-30 Ishaq Khalid S. 9-[(5-dihydroxyboryl)-pentyl] purines, useful as an inhibitor of inflammatory cytokines
WO2002088079A2 (en) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Dual inhibitors of pde 7 and pde 4
EP1404871A4 (en) 2001-05-23 2006-10-04 Sloan Kettering Inst Cancer METHOD FOR THE TREATMENT OF CANCER IN CONNECTION WITH INCREASED HER 2 VALUES
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
EP1478322A4 (en) 2001-06-22 2007-08-08 Pharmasset Ltd Beta-2'-OR 3'-HALONUCLEOSIDES
JP4381804B2 (en) 2001-06-27 2009-12-09 サイクラセル リミテッド 2,6,9-substituted purine derivatives and their use in the treatment of proliferative diseases
US6962991B2 (en) 2001-09-12 2005-11-08 Epoch Biosciences, Inc. Process for the synthesis of pyrazolopyrimidines
KR20040054692A (en) 2001-09-24 2004-06-25 콘포마 세러퓨틱스 코포레이션 Process for preparing 17-allyl amino geldanamycin (17-aag) and other ansamycins
DE60230818D1 (en) 2001-09-24 2009-02-26 Imp Innovations Ltd PYY3-36 FOR REDUCING OR PREVENTING GREASE LUBRICITY
JP2003113181A (en) 2001-10-04 2003-04-18 Sumika Fine Chemicals Co Ltd Method for producing 6-halopurine
DE10152275A1 (en) 2001-10-23 2003-04-30 Bayer Ag Process for the electrolysis of aqueous solutions of hydrogen chloride
EP1440072A4 (en) 2001-10-30 2005-02-02 Conforma Therapeutic Corp Purine analogs having hsp90-inhibiting activity
AU2002356922A1 (en) 2001-11-09 2003-05-26 Conforma Therapeutics Corporation Hsp90-inhibiting zearalanol compounds and methods of producing and using same
EP1519735A4 (en) 2001-12-12 2006-01-11 Conforma Therapeutic Corp TESTS AND ENFORCEMENTS FOR DETERMINING AND MODULATING HSP90 BINDING ACTIVITY
DE60327994D1 (en) 2002-02-08 2009-07-30 Conforma Therapeutics Corp ANSAMYCINE WITH IMPROVED PHARMACOLOGICAL AND BIOLOGICAL PROPERTIES
JP2004018453A (en) 2002-06-14 2004-01-22 Sumika Fine Chemicals Co Ltd Alkynylpurine compound and its manufacturing method
CN1688580A (en) 2002-08-08 2005-10-26 记忆药物公司 2-Trifluoromethyl-6-aminopurine derivatives as phosphodiesterase 4 inhibitors
GB0219746D0 (en) * 2002-08-23 2002-10-02 Inst Of Ex Botany Ascr Azapurine derivatives
WO2004024082A2 (en) 2002-09-13 2004-03-25 Irm, Llc Highly specific modulators of gtpases for target validation
RU2005108601A (en) 2002-09-26 2006-01-20 Эл Джи Лайф Сайенсиз Лтд. (Kr) (+) - TRANS-ISOMERS (1-PHOSPHONOMETOXY-2-ALKYL CYCLOPROPYL) METHYL NUCLEOSIDE DERIVATIVES, METHOD FOR PRODUCING THEIR STEREOISOMERS AND APPLICATION OF THESE COMPOUNDS AS A RELATED TO
US7601694B2 (en) * 2003-02-20 2009-10-13 New York University CLK-peptide and SLK-peptide
EP1781659B1 (en) * 2003-07-16 2008-11-05 Janssen Pharmaceutica N.V. Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
PT1658292E (en) * 2003-07-16 2007-10-25 Janssen Pharmaceutica Nv Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
US7579332B2 (en) 2003-07-30 2009-08-25 Gilead Sciences, Inc. Nucleobase phosphonate analogs for antiviral treatment
US20050054614A1 (en) 2003-08-14 2005-03-10 Diacovo Thomas G. Methods of inhibiting leukocyte accumulation
US20050043239A1 (en) * 2003-08-14 2005-02-24 Jason Douangpanya Methods of inhibiting immune responses stimulated by an endogenous factor
BRPI0414533A (en) * 2003-09-18 2006-11-07 Conforma Therapeutics Corp compound, pharmaceutical composition, and methods for inhibiting an hsp90 and treating an individual having an hsp90 mediated disorder
EP1772454A4 (en) * 2004-07-23 2009-02-25 Mitsubishi Tanabe Pharma Corp BICYCLIC NITROGEN COMPOUND
WO2007035963A2 (en) * 2005-09-23 2007-03-29 Conforma Therapeutics Corporation Anti-tumor methods using multi drug resistance independent synthetic hsp90 inhibitors
US9809805B2 (en) 2015-03-13 2017-11-07 Acro Biotech Co., Ltd. Zinc binding fusion protein of glutathione S-transferase and metallothionein

Cited By (4)

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CN116332940A (en) * 2023-02-14 2023-06-27 广西民族大学 A kind of 7-deazapurine derivative and its preparation method and application

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